Sequestered antagonist formulations

ABSTRACT

Disclosed is an oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the mean Cmax of the antagonist after single dose oral administration of the dosage form after tampering to the mean Cmax of antagonist after single dose oral administration of an intact dosage form is at least 1.5:1.

This application is a continuation of U.S. patent application Ser. No.11/352,900, filed on Feb. 13, 2006, which is a continuation of U.S.patent application Ser. No. 10/214,408, filed on Aug. 6, 2002, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/310,533,filed on Aug. 6, 2001, the disclosures of which are hereby incorporatedby reference in their entireties.

BACKGROUND OF THE INVENTION

Opioid formulations are sometimes the subject of abuse. A particulardose of oxycodone may be more potent when administered parenterally ascompared to the same dose administered orally. Also, some formulationscan be tampered with to provide the opioid agonist contained thereinbetter available for illicit use. For example, a controlled releaseopioid agonist formulation can be crushed to provide the opioidcontained therein available for immediate release upon oral orparenteral administration.

Opioid antagonists have been combined with certain opioid agonists todeter the parenteral abuse of opioid agonists. In the prior art, thecombination of immediate release pentazocine and naloxone has beenutilized in tablets available in the United States, commerciallyavailable as Talwin® Nx from Sanofi-Winthrop. Talwin® NX containsimmediate release pentazocine hydrochloride equivalent to 50 mg base andnaloxone hydrochloride equivalent to 0.5 rug base. A fixed combinationtherapy comprising tilidine (50 mg) and naloxone (4 mg) has beenavailable in Germany for the management of pain since 1978 (Valoron® N,Goedecke). A fixed combination of buprenorphine and naloxone wasintroduced in 1991 in New Zealand (Temgesic® Nx, Reckitt & Colman) forthe treatment of pain.

Purdue Pharma L.P currently markets sustained-release oxycodone indosage forms containing 10, 20, 40 and 80 mg oxycodone hydrochlorideunder the tradename OxyContin.

U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656.295 disclosesustained release oxycodone formulations.

U.S. Pat. Nos. 4,769,372 and 4,785,000 to Kreek describe methods oftreating patients suffering from chronic pain or chronic cough withoutprovoking intestinal dysmotility by administering 1 to 2 dosage unitscomprising from about 1.5 to about 100 mg of opioid analgesic orantitussive and from about 1 to about 18 mg of an opioid antagonisthaving little to no systemic antagonist activity when administeredorally, from 1 to 5 times daily.

U.S. Pat. No. 5,472,943 to Crain et al. describes methods of enhancingthe analgesic potency of bimodally acting opioid agonists byadministering the agonist with an opioid antagonist.

All documents cited herein, including the foregoing are incorporated byreference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the invention to provide an oral dosage form of anopioid agonist that is useful for decreasing the potential for abuse ofthe opioid agonist contained therein.

It is an object of a preferred embodiment of the invention to provide anoral dosage form of an opioid agonist that is useful for decreasing thepotential abuse of the opioid agonist without affecting the analgesiceffects of the opioid agonist or incurring the risk of precipitatingwithdrawal.

It is an object of a preferred embodiment of the invention to provide anoral dosage form of an opioid agonist that is resistant to misuse, abuseor diversion, wherein said resistance does not depend on individualpatient-specific differences in the effects of co-administered opioidagonist and antagonist mixtures.

It is an object of a preferred embodiment of the invention to provide anoral dosage form containing an effective dose of an opioid agonist alongwith a dose of opioid antagonist which does not change the analgesicefficacy of the opioid agonist when the dosage form is orallyadministered intact, but which can prevent abuse if the dosage form istampered with by interfering with the effect of the opioid agonist.

It is an object of a preferred embodiment of the invention to provide amethod for preventing abuse of an oral opioid dosage form where thedosage form also includes a dose of opioid antagonist which issequestered, e.g., is not bioavailable when the dose is administeredintact but is bioavailable when the dosage form is tampered with (e.g.,in an attempt to misuse the dose of opioid analgesic).

It is a further object of a preferred embodiment of the invention toprovide oral dosage forms that are intended for or are suitable for usein the management of acute or chronic pain where alteration of theopioid agonist's analgesic affects must be avoided such as in cases oftolerance, physical dependence or individual variability in hepaticmetabolism or physiology.

It is a further object of a preferred embodiment of the invention toprovide a method of treating pain in human patients with an oral dosageform of an opioid agonist while reducing its misuse by oral, parenteral,intranasal and/or sublingual route.

Some or all of the above objects and others are achieved by embodimentsof the present invention, which is directed in part to an oral dosageform comprising an opioid agonist and an opioid antagonist, wherein theopioid antagonist is present in a substantially non-releasable form(i.e., “sequestered”). In preferred embodiments, the dosage formcontains an orally therapeutically effective amount of the opioidagonist, the dosage form providing a desired analgesic effect. Becausethe opioid antagonist is present in a substantially non-releasable form,it does not substantially block the analgesic effect of the opioidagonist when the dosage form is orally administered intact, and does notpose a risk of precipitation of withdrawal in opioid tolerant ordependent patients.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Cmax of the antagonist after single doseoral administration of the dosage form after tampering to the mean Cmaxof antagonist after single dose oral administration of an intact dosageform is at least 1.5:1.

In certain embodiments of the invention, the ratio of the mean Cmax ofantagonist after single oral administration of a tampered dosage form toan intact dosage form is at least 3:1, at least 4.5:1, at least 8:1, atleast 10:1, at least 100:1, at least 500:1 or at least 1000:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Cmax of the antagonist after single doseoral administration of the dosage form after tampering to the mean Cmaxof antagonist after single dose oral administration of an intact dosageform of the present invention is at least 1.5:1; wherein the opioidantagonist comprises naltrexone or a pharmaceutically acceptable saltthereof. In certain embodiments, the intact dosage form provides a meanCmax of naltrexone of 30 pg/ml or less, 15 pg/ml or less, 10 pg/ml orless, 6 pg/ml or less, 3 pg/ml or less or 1 pg/ml or less based on adosage form containing 1 mg of naltrexone hydrochloride or an equivalentamount of naltrexone base or a pharmaceutically acceptable salt thereofother than the hydrochloride salt.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Cmax of the antagonist after single doseoral administration of an immediate release reference product containingan equivalent amount of antagonist to the mean Cmax of antagonist aftersingle dose oral administration of an intact dosage form of the presentinvention is at least 2:1.

In certain embodiments of the invention, the ratio of the mean Cmax ofthe antagonist after single dose oral administration of an immediaterelease reference product containing an equivalent amount of antagonistto the mean Cmax of antagonist after single dose oral administration ofan intact dosage form of the present invention is at least 4:1, at least8:1, at least 12:1, at least 25:1, at least 150:1 or at least 2000:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Cmax of the antagonist after single doseoral administration of an immediate release reference product containingan equivalent amount of antagonist to the mean Cmax of antagonist aftersingle dose oral administration of an intact dosage form of the presentinvention is at least 2:1; wherein the opioid antagonist comprisesnaltrexone or a pharmaceutically acceptable salt thereof. In certainembodiments, the intact dosage form provides a mean Cmax of naltrexoneof 30 pg/ml or less, 15 pg/ml or less, 10 pg/ml or less, 6 pg/ml orless, 3 pg/ml or less or 1 pg/ml or less based on a dosage formcontaining 1 mg of naltrexone hydrochloride or an equivalent amount ofnaltrexone base or a pharmaceutically acceptable salt thereof other thanthe hydrochloride salt.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean AUCt of the antagonist after single doseoral administration of the dosage form after tampering to the mean AUCtof antagonist after single dose oral administration of an intact dosageform is at least 1.5:1.

In certain embodiments of the invention, the ratio of the mean AUCt ofthe antagonist after single dose oral administration of the dosage formafter tampering to the mean AUCt of antagonist after single dose oraladministration of an intact dosage form is at least 3:1; at least 4.5:1;at least 8:1; at least 10:1; at least 100:1; or at least 500:1. Incertain embodiments, the ration is less than about 1000:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean AUCt of the antagonist after single doseoral administration of the dosage form after tampering to the mean AUCtof antagonist after single dose oral administration of an intact dosageform of the present invention is at least 1.5:1; wherein the opioidantagonist comprises naltrexone or a pharmaceutically acceptable saltthereof. In certain embodiments, the intact dosage form provides an AUCtof naltrexone of 400 pg·h/ml or less; 350 pg·h/ml or less; 225 pg·h/mlor less; 100 pg·h/ml or less; 50 pg·h/ml or less; or 25 pg·h/ml or lessbased on a dosage form containing 1 mg of naltrexone hydrochloride or anequivalent amount of naltrexone base or a pharmaceutically acceptablesalt thereof other than the hydrochloride salt.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean AUCt of the antagonist after single doseoral administration of an immediate release reference product containingan equivalent amount of antagonist to the mean AUCt of antagonist aftersingle dose oral administration of an intact dosage form of the presentinvention is at least 1.6:1.

In certain embodiments of the invention, the ratio of the mean AUCt ofthe antagonist after single dose oral administration of an immediaterelease reference product containing an equivalent amount of antagonistto the mean AUCt of antagonist after single dose oral administration ofthe intact dosage form is at least 4:1; at least 7:1; at least 12:1; atleast 25:1; at least 150:1. In certain embodiments, the ration is lessthan about 2000:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising opioid agonist in releasableform and (ii) a sequestered opioid antagonist which is substantially notreleased when the dosage form is administered intact, such that theratio of the mean AUCt of the antagonist after single dose oraladministration of an immediate release reference product containing anequivalent amount of antagonist to the mean AUCt of antagonist aftersingle dose oral administration of an intact dosage form is at least1.6:1; wherein the opioid antagonist comprises naltrexone or apharmaceutically acceptable salt thereof. In certain embodiments, theintact dosage form provides an AUCt of naltrexone of 400 pg·h/ml orless; 350 pg·h/ml or less; 225 pg·h/ml or less; 100 pg·h/ml or less; 50pg·h/ml or less; or 25 pg·h/ml or less based on a dosage form containing1 mg of naltrexone hydrochloride or an equivalent amount of naltrexonebase or a pharmaceutically acceptable salt thereof other than thehydrochloride salt.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Tmax of the antagonist after single doseoral administration of the intact dosage form to the mean Tmax ofantagonist after single dose oral administration of a dosage form aftertampering is at least 1.5.

In certain embodiments of the invention, the ratio of the mean Tmax ofthe antagonist after single dose oral administration of the intactdosage form to the mean Tmax of antagonist after single dose oraladministration of a dosage form after tampering is at least 3:1; atleast 4:1; at least 8:1; at least 10:1; at least 50:1. In certainembodiments, the ratio is less than about 100:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Tmax of the antagonist after single doseoral administration of the intact dosage form to the mean Tmax ofantagonist after single dose oral administration of a dosage form aftertampering is at least 1.5; wherein the opioid antagonist comprisesnaltrexone or a pharmaceutically acceptable salt thereof. In certainembodiments, the intact dosage form provides a Tmax of naltrexone ofabout 0.75 hours to about 36 hours; about 1 hour to about 30 hours;about 2 hour to about 20 hours; of about 3 hours to about 20 hours;about 5 hours to about 15 hours; or about 6 hours to about 10 hours.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Tmax of the antagonist after single doseoral administration of the intact dosage form to the mean Tmax ofantagonist after single dose oral administration of an immediate releasereference standard is at least 2:1.

In certain embodiments of the invention, the ratio of the mean Tmax ofthe antagonist after single dose oral administration of the intactdosage form to the mean Tmax of antagonist after single dose oraladministration of an immediate release reference standard is at least4:1; at least 10:1; at least 20:1; at least 50:1; or at least 100:1. Incertain embodiments, the ration is less than about 150:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the mean Tmax of the antagonist after single doseoral administration of the intact dosage form to the mean Tmax ofantagonist after single dose oral administration of an immediate releasereference standard is at least 2:1; wherein the opioid antagonistcomprises naltrexone or a pharmaceutically acceptable salt thereof. Incertain embodiments, the intact dosage form provides a Tmax ofnaltrexone of about 0.75 hours to about 36 hours; about 1 hour to about30 hours; about 2 hour to about 20 hours; of about 3 hours to about 20hours: about 5 hours to about 15 hours; or about 6 hours to about 10hours.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the Cmax of the antagonist after single dose oraladministration of the dosage form to an individual patient aftertampering to the Cmax of antagonist after single dose oraladministration to an individual patient of an intact dosage form is atleast 1.5:1.

In certain embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the Cmax of the antagonist after single dose oraladministration to an individual patient of an immediate releasereference product containing an equivalent amount of antagonist to theCmax of antagonist after single dose oral administration to anindividual patient of an intact dosage form is at least 2:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the AUCt of the antagonist after single dose oraladministration to an individual patient of the dosage form aftertampering to the AUCt of antagonist after single dose oraladministration of an intact dosage form to an individual patient is atleast 1.5:1.

In certain embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the AUCt of the antagonist after single dose oraladministration to an individual patient of an immediate releasereference product containing an equivalent amount of antagonist to theAUCt of antagonist after single dose oral administration to anindividual patient of an intact dosage form is at least 1.6:1.

In other embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the Tmax of the antagonist after single dose oraladministration to an individual patient of the intact dosage form to theTmax of antagonist after single dose oral administration to anindividual patient of an dosage form after tampering is at least 1.5:1

In certain embodiments, the oral dosage form of the present invention isdirected to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the Tmax of the antagonist after single dose oraladministration to an individual patient of the intact dosage form to theTmax of antagonist after single dose oral administration to anindividual patient of an immediate release reference standard is atleast 2:1.

In other embodiments, the invention is directed to any single embodimentabove in combination with any single or multiple embodiments above,including embodiments of combinations of Tmax, AUCt and Cmax,irrespective of mean or individual data.

In certain embodiments, the invention is directed to any compositionexhibiting any pharmacokinetic value, range or ratio that can be gleanedby one skilled in the art from the tables and examples of the presentapplication.

In other embodiments, the invention is directed to a method of treatingpain comprising administering a dosage form of any of the aboveembodiments.

In certain embodiments, the invention is directed to a method ofpreparing a dosage form comprising combining an opioid agonist and anopioid antagonist with a pharmaceutically acceptable excipient to for adosage form of any of the above embodiments.

In other embodiments, the invention is directed to a method ofpreventing abuse of a dosage form comprising preparing a dosage form ofany of the above embodiments.

In other embodiments, the invention is directed to an oral dosage formcomprising an opioid agonist; and an orally-bioavailable opioidantagonist in a substantially non-releasable form; wherein the agonistand antagonist are at least partially interdispersed.

In embodiments of the invention wherein the antagonist is in the form ofmultiparticulates coated with a sequestering material, themultiparticulates can be in the form of inert beads coated with theantagonist and overcoated with the material, or alternatively in theform of a granulation comprising the antagonist and the material. Themultiparticulates can be dispersed in a matrix comprising the opioidagonist or contained in a capsule with the opioid agonist.

In embodiments of the invention wherein the antagonist is dispersed in amatrix comprising a sequestering material, which substantially preventsthe release of the antagonist, the matrix can be in the form of pellets.The pellets can be dispersed in another matrix comprising the opioidagonist or contained in a capsule with the opioid agonist.

In other embodiments of the invention, part of the antagonist is in amatrix and/or part of the antagonist is in a coated bead.

The invention is also directed to methods of preventing abuse of anopioid agonist utilizing the dosage forms disclosed herein. The methodcan comprise providing the opioid agonist in an oral dosage formtogether with an opioid antagonist, wherein the opioid antagonist ispresent in a form which is in a substantially non-releasable form upondigestion when the integrity of the dosage form is maintained untildigestion begins, but which becomes bioavailable if subjected totampering (e.g., crushing, shear forces which break up the dosage form,etc., solvents or temperatures of greater than 45° C.).

Another embodiment of the invention is directed to a method ofdecreasing the abuse of an opioid agonist in an oral dosage form,comprising preparing an oral dosage form as disclosed herein. Forexample, the method can comprise preparing a dosage form which comprises(i) an orally therapeutically effective amount of an opioid agonist and(ii) an opioid antagonist in a substantially non-releasable form suchthat said dosage form provides a desired analgesic effect and saidantagonist does not substantially block the analgesic effect of theopioid agonist when said dosage form is administered orally intact. Inalternative embodiments, the effect of the opioid agonist is at leastpartially blocked when said dosage form is tampered with, e.g., chewed,crushed or dissolved in a solvent, and administered orally,intranasally, parenterally or sublingually.

The invention is also directed to a method of treating pain with thedosage forms disclosed herein. The method can comprise providing an oraldosage form containing an opioid agonist in a releasable form and anopioid antagonist in substantially non-releasable form; and orallyadministering the intact oral dosage form.

Another embodiment of the invention is directed to a method of treatingpain with the disclosed dosage forms. In certain embodiments, the methodof treating pain in patients with a dosage form having less abusepotential comprises providing an oral dosage form containing areleasable form of an opioid agonist and a substantially non-releasableform of an opioid antagonist; and orally administering the oral dosageform to provide a blood plasma level of agonist greater than the minimumanalgesic concentration of the opioid agonist.

The invention is also directed to methods of preparing the dosage formsdisclosed herein. In certain embodiments, the invention comprises amethod of preparing an oral dosage form comprising pretreating an opioidantagonist to render it substantially non-releasable; and combining thepretreated antagonist with a releasable form of an opioid agonist in amanner that maintains the integrity of the non-releasable form of theantagonist.

Certain embodiments of the invention are directed to formulationswherein the agonist and antagonist are interdispersed and are notisolated from each other in two distinct layers. However in certainembodiments, the agonist and antagonist are partially interdispersed

The term “analgesic effectiveness” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with a tolerable level of side effects, as determined by the humanpatient. The phrase “not substantially blocking the analgesic effect ofan opioid agonist” means that the opioid antagonist does not block theeffects of the opioid agonist in sufficient degree as to render thedosage form therapeutically less effective for providing analgesia.

The term “an opioid antagonist in a substantially non-releasable form”refers to an opioid antagonist that is not released or substantially notreleased at one hour after the intact dosage form containing both opioidagonist and the opioid antagonist is orally administered (i.e., withouthaving been tampered with). Such a dosage form is also referred to ascomprising a “sequestered antagonist”.

Although the preferred embodiments of the invention comprise an opioidantagonist in a form that completely prevents the release of the opioidantagonist, the invention also includes an antagonist in a substantiallynon-releasable form. The term “substantially not released” refers to theantagonist that might be released in a small amount, as long as theamount released does not affect or does not significantly affectanalgesic efficacy when the dosage farm is orally administered to humansas intended.

In certain preferred embodiments of the invention, the substantiallynon-releasable form of the antagonist is resistant to laxatives (e.g.,mineral oil) used to manage delayed colonic transit and to achlorhydricstates.

In certain embodiments, the substantially non-releasable form of anopioid antagonist comprises an opioid antagonist that is formulated withone or more of pharmaceutically acceptable hydrophobic material, suchthat the antagonist is not released or substantially not released duringits transit through the gastrointestinal tract when administered orallyas intended, without having been tampered with.

In certain embodiments of the present invention, the substantiallynon-releasable form of the opioid antagonist is vulnerable tomechanical, thermal and/or chemical tampering, e.g., tampering by meansof crushing, shearing, grinding, chewing and/or dissolution in a solventin combination with heating (e.g., greater than about 45° C.) of theoral dosage form. When thus tampered with, the integrity of thesubstantially non-releasable form of the opioid antagonist will becompromised, and the opioid antagonist will be made available to bereleased. In certain embodiments, when the dosage form is chewed,crushed or dissolved and heated in a solvent, and administered orally,intranasally, parenterally or sublingually, the analgesic or euphoriceffect of the opioid is reduced or eliminated. In certain embodiments,the effect of the opioid agonist is at least partially blocked by theopioid antagonist. In certain other embodiments, the effect of theopioid agonist is substantially blocked by the opioid antagonist.

The term “tampering” means any manipulation by mechanical, thermaland/or chemical means which changes the physical properties of thedosage form, e.g., to liberate the opioid agonist for immediate releaseif it is in sustained release form, or to make the opioid agonistavailable for inappropriate use such as administration by an alternateroute, e.g., parenterally. The tampering can be, e.g., by means ofcrushing, shearing, grinding, chewing, dissolution in a solvent, heating(e.g., greater than about 45° C.), or any combination thereof.

The term “at least partially blocking the opioid effect,” is defined forpurposes of the present invention to mean that the opioid antagonist atleast significantly blocks the euphoric effect of the opioid agonist,thereby reducing the potential for abuse of the opioid agonist in thedosage form.

In certain preferred embodiments of the present invention, thesubstantially non-releasable form of the opioid antagonist comprisesopioid antagonist particles in a coating that substantially prevents therelease of the antagonist. In preferred embodiments, the coatingcomprising one or more of pharmaceutically acceptable hydrophobicmaterial. The coating is preferably impermeable to the opioid antagonistcontained therein and is insoluble in the gastrointestinal system, thussubstantially preventing the release of the opioid antagonist when thedosage form is administered orally as intended.

Accordingly, when the oral dosage form is not tampered with as tocompromise the integrity of the coating, the opioid antagonist containedtherein will not be substantially released during its first hour oftransit through the gastrointestinal system, and thus would not beavailable for absorption. In certain preferred embodiments of thepresent invention, the hydrophobic material comprises a cellulosepolymer or an acrylic polymer that is insoluble in the gastrointestinalfluids and impermeable to the opioid antagonist.

The term “particles” of opioid antagonist, as used herein, refers togranules, spheroids, beads or pellets comprising the opioid antagonist.In certain preferred embodiments, the opioid antagonist particles areabout 0.2 to about 2 mm in diameter, more preferably about 0.5 to about2 mm in diameter.

In certain embodiments of the present invention, the oral dosage formfurther comprises an opioid antagonist in a releasable form and is thuscapable of being released from the oral dosage form when orallyadministered, the ratio of the opioid agonist to the releasable form ofthe opioid antagonist being such that the dosage form, when administeredorally, is analgesically effective. For example, when the opioidantagonist is coated with a coating that substantially prevents itsrelease, and is then mixed with an opioid agonist and compressed intotablets, certain amounts of the coating might be cracked, thus exposingthe opioid antagonist to be released upon oral administration.

Preferably, the opioid agonist useful for the present invention may beselected from the group consisting of morphine, hydromorphone,hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone andmixtures thereof. Preferred examples of the opioid antagonist useful forthe present invention includes naltrexone, naloxone, nalmefene,cyclazacine, levallorphan, pharmaceutically acceptable salts thereof andmixtures thereof.

In certain embodiments of the present invention, the ratio of the opioidagonist and the opioid antagonist, present in a substantiallynon-releasable form, is about 1:1 to about 50:1 by weight, preferablyabout 1:1 to about 20:1 by weight or 15:1 to about 30:1. The weightratio of the opioid agonist to opioid antagonist, as used in thisapplication, refers to the weight of the active ingredients. Thus, forexample, the weight of the opioid antagonist excludes the weight of thecoating or matrix that renders the opioid antagonist substantiallynon-releasable, or other possible excipients associated with theantagonist particles. In certain preferred embodiments, the ratio isabout 1:1 to about 10:1 by weight. Since the opioid antagonist is in asubstantially non-releasable from, the amount of such antagonist withinthe dosage form may be varied more widely than the opioidagonist/antagonist combination dosage forms where both are available forrelease upon administration as the formulation does not depend ondifferential metabolism or hepatic clearance for proper functioning. Forsafety reasons, the amount of the opioid antagonist present in asubstantially non-releasable form is selected as not to be harmful tohumans even if fully released by tampering with the dosage form.

In certain preferred embodiments of the present invention, the opioidagonist comprises hydrocodone, oxycodone or pharmaceutically acceptablesalts thereof and the opioid antagonist, present in a substantiallynon-releasable form, comprises naloxone, naltrexone or pharmaceuticallyacceptable salts thereof.

The oral dosage form containing an opioid agonist in combination with asubstantially non-releasable form of an opioid antagonist includes, butis not limited to, tablets or capsules. The dosage forms of the presentinvention may include any desired pharmaceutical excipients known tothose skilled in the art. The oral dosage forms may further provide animmediate release of the opioid agonist. In certain embodiments, theoral dosage forms of the present invention provide a sustained releaseof the opioid agonist contained therein. Oral dosage forms providingsustained release of the opioid agonist may be prepared in accordancewith formulations/methods of manufacture known to those skilled in theart of pharmaceutical formulation, e.g., via the incorporation of asustained release carrier into a matrix containing the substantiallynon-releasable form of an opioid antagonist; or via a sustained releasecoating of a matrix containing the opioid agonist and the substantiallynon-releasable form of the opioid antagonist.

The benefits of the abuse-resistant dosage form are especially great inconnection with oral dosage forms of strong opioid agonists (e.g.,oxycodone or hydrocodone), which provide valuable analgesics but areprone to being abused. This is particularly true for sustained releaseopioid agonist products, which have a large dose of a desirable opioidagonist intended to be released over a period of time in each dosageunit. Drug abusers take such sustained-release product and crush, grind,extract or otherwise damage the product so that the full contents of thedosage form become available for immediate absorption. Since suchtampering of the dosage form of the invention results in the opioidantagonist also becoming available for absorption, the present inventionprovides a means for frustrating such abuse. In addition, the presentinvention addresses the risk of overdose to ordinary patients from“dumping” effect of the full dose of the opioid agonist if the productis accidentally chewed or crushed.

The term “sustained release” is defined for purposes of the presentinvention as the release of the opioid agonist from the oral dosage format such a rate that blood (e.g., plasma) concentrations (levels) aremaintained within the therapeutic range (above the minimum effectiveanalgesic concentration or “MEAC”) but below toxic levels over a periodof 8 to 24 hours, preferably over a period of time indicative of atwice-a-day or a once-a-day formulation.

The invention may provide for a safer product (e.g., less respiratorydepression), if the product is misused, as well as one with less risk ofabuse.

In certain embodiments, a combination of two opioid agonists is includedin the formulation. In further embodiments, one or more opioid agonistis included and a further non-opioid drug is also included. Suchnon-opioid drugs would preferably provide additional analgesia, andinclude, for example, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs (“MAIDS”), NMDA antagonists, andcyclooxygenase-II inhibitors (“COX-II inhibitors”).

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, or antihistamine drugs, and the like.

For purposes of the present invention, the term “opioid agonist” isinterchangeable with the term “opioid” or “opioid analgesic” and shallinclude combinations of more than one opioid agonist, and also includethe base of the opioid, mixed agonist-antagonists, partial agonists,pharmaceutically acceptable salts thereof, stereoisomers thereof, ethersand esters thereof, and mixtures thereof.

For purposes of the present invention, the term “opioid antagonist”shall include combinations of more than one opioid antagonist, and alsoinclude the base, pharmaceutically acceptable salts thereof,stereoisomers thereof, ethers and esters thereof, and mixtures thereof.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed opioidagonists and antagonists. The pharmaceutically acceptable salts include,but are not limited to metal salts such as sodium salt, potassium salt,secium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

Some of the opioid agonists and antagonists disclosed herein may containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms. The present invention isalso meant to encompass all such possible forms as well as their racemicand resolved forms and mixtures thereof. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended to includeboth E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms is space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The term “immediate release reference product” means a formulation whichreleases at least 90% active within 15 minutes when dissolution testedin 900 mL 0.1N HCl using a USP Type II (Paddle) at 50 rpm at 37° C.(e.g., the formulation of Example 3).

The present invention is further directed to a method of decreasing thepotential for abuse of an opioid agonist in an oral dosage form. Themethod comprises providing the opioid agonist in an oral dosage form asdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the study of Example 4.

FIG. 2 is a graphical representation of the non-adjusted mean plasmanaltrexone concentrations (ng/mL) over time for Group A.

FIG. 3 is a graphical representation of the non-adjusted mean plasmanaltrexone concentrations (ng/mL) over time for Group B.

DETAILED DESCRIPTION OF THE INVENTION

It has been postulated that there exists at least three subspecies ofopioid receptors, designated mu, kappa, and delta. Within thisframework, the mu receptor is considered to be involved in theproduction of superspinal analgesia, respiratory depression, euphoria,and physical dependence. The kappa receptor is considered to be involvedin inducing spinal analgesia, miosis and sedation. Activation of thegamma receptors causes dysphoria and hallucinations, as well asrespiratory and vasomotor stimulatory effects. A receptor distinct fromthe mu receptor and designated gamma has been described in the mouse vasdeferens, Lord, et al. Nature, 1977, 267, 495-99. Opioid agonists arethought to exert their agonist actions primarily at the mu receptor andto a lesser degree at the kappa receptor. There are a few drugs thatappear to act as partial agonists at one receptor type or another. Suchdrugs exhibit a ceiling effect. Such drugs include nalorphine, propiram,and buprenorphine. Still other drugs act as competitive antagonists atthe mu receptor and block the effects of morphine-like drugs, byexerting their actions at the kappa and omega receptors. The termagonist-antagonist has evolved to describe such mechanism of actions.

The present invention is directed to a controlled release opioidanalgesic, similar in analgesic spectrum to existing controlled-releaseopioid analgesics, which is formulated to reduce and minimize misuse,abuse and diversion. In certain embodiments, these characteristics areconferred by the inclusion of an opioid antagonist such as naltrexonewhich is itself formulated in a unique controlled release matrix. Theproperties of this formulation are developed to liberate the antagonistin conditions of misuse or tampering yet a negligible amount ofantagonist would be released (an amount which does not affect theanalgesia experienced by the patient) under the prescribed conditions ofuse.

In certain embodiments of the invention, the release for the antagonistcomponent of the formulation is expressed in terms of a ratio of therelease achieved after tampering, e.g., by crushing or chewing, relativeto the amount released from the intact formulation of the presentinvention. In certain embodiments of the invention, the release for theantagonist component of the formulation is expressed in terms of a ratioof the release achieved by an immediate release reference product to theamount released from the intact formulation of the present invention.

The present invention provides an oral dosage form of opioid agonistuseful for decreasing the potential for abuse of the opioid agonistcontained therein. The present invention includes an oral dosage formcomprising an orally therapeutically effective amount of an opioidagonist in combination with an opioid antagonist. The opioid antagonistis present in a substantially non-releasable form.

In certain preferred embodiments, the opioid antagonist in asubstantially non-releasable form comprises opioid antagonist particlescoated with a coating that substantially prevents its release. Inpreferred embodiments, such coating surrounds the antagonist particlesand is impermeable to the drug and is insoluble in the gastrointestinalsystem. When the dosage form of the present invention is orallyadministered to humans, the opioid antagonist is not substantiallyreleased from the coating and is, therefore, not available forabsorption into the body. Thus, the opioid antagonist, although presentin the dosage form, does not substantially block the analgesiceffectiveness of the opioid agonist. However, if the oral dosage form ofthe present invention is tampered with as to compromise the integrity ofthe coating, the opioid antagonist contained therein would be madeavailable to at least partially block the effect of the opioid agonist.This characteristic decreases the potential for abuse or diversion ofthe opioid agonist in the oral dosage form. For example, if one attemptsto abuse the drug contained in the oral dosage form of the presentinvention by, e.g., chewing, crushing, grinding or dissolving it in asolvent with heat (e.g., greater than about 45° C. to about 50° C.), thecoating will be damaged and will no longer prevent the opioid antagonistfrom being released. Upon administration, the opioid antagonist will bereleased and significantly block the euphoric effect of the opioidagonist.

In certain embodiments of the invention, the ratio of the opioid agonistto the coated opioid antagonist is such that when the oral dosage formis tampered with as to compromise the integrity of the coating thatrenders the opioid antagonist substantially non-releasable, the euphoriceffect of the agonist would be negated by the opioid antagonist whenmisused by a human subject orally, parenterally, intranasally orsublingually. In certain preferred embodiments of the invention, theeuphoric effect of the opioid agonist would be negated by the opioidantagonist when misused parenterally or sublingually.

The present invention also includes an oral dosage form which comprisesa releasable form of an opioid antagonist, along with an opioid agonistand a sequestered antagonist, the ratio of the agonist to the releasableantagonist being such, when administered orally as intended, the oraldosage form is analgesically effective.

In certain other embodiments of the present invention, the opioidantagonist in a substantially non-releasable form comprises an opioidantagonist dispersed in a matrix that renders the antagonistsubstantially non-releasable, wherein the matrix comprises one or moreof a pharmaceutically acceptable hydrophobic material. The antagonist issubstantially not released from the matrix, thus is not made availableto be absorbed during its transit through the gastrointestinal system.

In certain other embodiments of the present invention, the opioidantagonist in a matrix that renders the antagonist substantiallynon-releasable comprises an opioid antagonist dispersed in amelt-extruded matrix, wherein the matrix comprises one or more of apharmaceutically acceptable hydrophobic material.

In preferred embodiments, opioid agonists useful in the presentinvention include, but are not limited to, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl andderivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium,oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sufentanil,tilidine, tramadol, mixtures of any of the foregoing, salts of any ofthe foregoing, and the like. In certain embodiments, the amount of theopioid agonist in the claimed opioid composition may be about 75 ng to750 mg.

In certain preferred embodiments, the opioid agonist is selected fromthe group consisting of hydrocodone, morphine, hydromorphone, oxycodone,codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine,fentanyl and derivatives thereof, dipipanone, heroin, tramadol,etorphine, dihydroetorphine, butorphanol, levorphanol, or salts thereofor mixtures thereof. In certain preferred embodiments, the opioidagonist is oxycodone or hydrocodone. Equianalgesic doses of theseopioids, in comparison to a 15 mg dose of hydrocodone, are set forth inTable A below:

TABLE A Equianalgesic Doses of Opioids Opioid Calculated Dose (mg)Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375Levorphanol 1.8 Meperdine 135.0 Methadone 9.0 Morphine 27.0

Although hydrocodone and oxycodone are effective in the management ofpain, there has been an increase in their abuse by individuals who arepsychologically dependent on opioids or who misuse opioids fornon-therapeutic reasons. Previous experience with other opioids hasdemonstrated a decreased abuse potential when opioids are administeredin combination with a narcotic antagonist especially in patients who areex-addicts. Weinhold L L, et al. Buprenorphine Alone and in Combinationwith Naltrexone in Non-Dependent Humans, Drug and Alcohol Dependence1992; 30:263-274; Mendelson J., et al., Buprenorphine and NaloxoneInteractions in Opiate-Dependent Volunteers, Clin Pharm Ther. 1996;60:105-114; both of which are hereby incorporated by reference. Thesecombinations, however, do not contain the opioid antagonist that is in asubstantially non-releasable form. Rather, the opioid antagonist isreleased in the gastrointestinal system when orally administered and ismade available for absorption, relying on the physiology of the host todifferentially metabolize the agonist and antagonist and negate theagonist effects.

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

Oral hydrocodone is also available in Europe (Belgium, Germany, Greece,Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. Aparenteral formulation is also available in Germany as an antitussiveagent. For use as an analgesic, hydrocodone bitartrate is commerciallyavailable in the United States only as a fixed combination withnon-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) forrelief of moderate or moderately severe pain.

A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine, or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of the opioid antagonist particlescoated with a coating that renders the antagonist substantiallynon-releasable.

Oxycodone, chemically known as4,5-expoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

Oxycodone is commercially available in the United States, e.g., asOxycontin® from Purdue Pharma L.P. as controlled-release tablets fororal administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodonehydrochloride, and as OxyIR™, also from Purdue Pharma L.P., asimmediate-release capsules containing 5 mg oxycodone hydrochloride. Thepresent invention is contemplated to encompass all such formulations,with the inclusion of an opioid antagonist in a substantiallynon-releasable form.

In preferred embodiments, the opioid antagonist of the present inventionincludes naltrexone, nalmefene, cyclazacine, levallorphan and mixturesthereof. In certain preferred embodiments, the opioid antagonist isnaloxone or naltrexone. In certain embodiments, the amount of the opioidantagonist, present in a substantially non-releasable form, may be about10 ng to 275 mg.

Naloxone is an opioid antagonist, which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to havesignificantly lower potency than as when parenterally administered. Oraldosage of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed. Weinberg, et al.,Sublingual Absorption of selected Opioid Analgesics, Clin PharmacolTher. (1988); 44:335-340.

Other opioid antagonists, for example, cyclazocine and naltrexone, bothof which have cyclopropylmethyl substitutions on the nitrogen, retainmuch of their efficacy by the oral route and their durations of actionare much longer, approaching 24 hours after oral doses.

In the treatment of patients previously addicted to opioids, naltrexonehas been used in large oral doses (over 100 mg) to prevent euphorigeniceffects of opioid agonists. Naltrexone has been reported to exert strongpreferential blocking action against mu over delta sites. Naltrexone isknown as a synthetic congener of oxymorphone with no opioid agonistproperties, and differs in structure from oxymorphone by the replacementof the methyl group located on the nitrogen atom of oxymorphone with acyclopropylmethyl group. The hydrochloride salt of naltrexone is solublein water up to about 100 mg/cc. The pharmacological and pharmacokineticproperties of naltrexone have been evaluated in multiple animal andclinical studies. See, e.g., Gonzalez J P, et al. Naltrexone: A reviewof its Pharmacodynamic and Pharmacokinetic Properties and TherapeuticEfficacy in the Management of Opioid Dependence. Drugs 1988; 35:192-213,hereby incorporated by reference. Following oral administration,naltrexone is rapidly absorbed (within 1 hour) and has an oralbioavailability ranging from 5-40%. Naltrexone's protein binding isapproximately 21% and the volume of distribution following single-doseadministration is 16.1 L/kg.

Naltrexone is commercially available in tablet form (Revia®, DuPont) forthe treatment of alcohol dependence and for the blockade of exogenouslyadministered opioids. See, e.g., Revia (naltrexone hydrochloridetablets). Physician's Desk Reference 51^(st) ed., Montvale, N.J.“Medical Economics” 1997; 51:957-959. A dosage of 50 mg Revia® blocksthe pharmacological effects of 25 mg IV administered heroin for up to 24hours.

It is known that when coadministered with morphine, heroin or otheropioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with narcotic addicts having good prognosis, as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

In certain embodiments of the present invention, ratio of the opioidagonist to the substantially non-releasable form of an opioid antagonistin the oral dosage form is such that the effect of the opioid agonist isat least partially blocked when the dosage form is chewed, crushed ordissolved in a solvent and heated, and administered orally,intranasally, parenterally or sublingually. Since the oral dosage formof the present invention, when administered properly as intended, wouldnot substantially release the opioid antagonist, the amount of suchantagonist may be varied more widely than if the opioid antagonist isavailable to be released into the gastrointestinal system upon oraladministration. For safety reasons, the amount of the antagonist presentin a substantially non-releasable form should not be harmful to humanseven if fully released. The ratio of particular opioid agonist toantagonist can be determined without undue experimentation by oneskilled in the art.

In certain embodiments of the present invention, the ratio of the opioidagonist to the opioid antagonist, present in a substantiallynon-releasable form, is about 1:1 to about 50:1 by weight, preferablyabout 1:1 to about 20:1 by weight. In certain preferred embodiments, theratio is about 1:1 to about 10:1 by weight. In a preferred embodiment ofthe invention, the opioid agonist comprises oxycodone or hydrocodone andis present in the amount of about 15-45 rag and the opioid antagonistcomprises naltrexone and is present in about 0.5-5 mg.

The oral dosage form of the present invention may further include, inaddition to an opioid agonist and antagonist, one or more drags that mayor may not act synergistically therewith. Thus, in certain embodiments,a combination of two opioid agonists may be included in the dosage form,in addition to the opioid antagonist. For example, the dosage form mayinclude two opioid agonists having different properties, such ashalf-life, solubility, potency, and a combination of any of theforegoing. In yet farther embodiments, one or more opioid agonist isincluded and a farther non-opioid drug is also included, in addition tothe opioid antagonist. Such non-opioid drugs would preferably provideadditional analgesia, and include, for example, aspirin, acetaminophen;non-steroidal anti-inflammatory drugs (“NSAIDS”), e.g., ibuprofen,ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists,e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine;cyclooxygenase-II inhibitors (“COX-II inhibitors”); and/or glycinereceptor antagonists.

In certain preferred embodiments of the present invention, the inventionallows for the use of lower doses of the opioid analgesic by virtue ofthe inclusion of an additional non-opioid agonist, such as an NSAID or aCOX-2 inhibitor. By using lower amounts of either or both drags, theside effects associated with effective pain management in humans arereduced.

Suitable non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Useful dosages of these drugs are well known tothose skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, d-methadone or pharmaceutically acceptable saltsthereof. For purposes of the present invention, the term “NMDAantagonist” is also deemed to encompass drugs that block a majorintracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM₁ or GT_(1b) a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et. al. patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.), hereby incorporated by reference.

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,474,995;5,639,780; 5,604.253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day are therapeuticallyeffective in combination with an opioid analgesic. Alternatively, about0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in combination with an opioid analgesic.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

Preparation of Opioid Antagonist in a Substantially Non-Releasable Form

In certain embodiments of the present invention, an opioid antagonist ina substantially non-releasable form may be prepared by combining theantagonist with one or more of a pharmaceutically acceptable hydrophobicmaterial. For example, opioid antagonist particles may be coated withcoating that substantially prevents the release of the antagonist, thecoating comprising the hydrophobic materials(s). Another example wouldbe an opioid antagonist that is dispersed in a matrix that renders theantagonist to be substantially non-releasable, the matrix comprising thehydrophobic materials(s). In certain embodiments, the pharmaceuticalacceptable hydrophobic material comprises a cellulose polymer selectedfrom the group consisting of ethylcellulose, cellulose acetate,cellulose propionate (lower, medium or higher molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate and cellulose triacetate. An example of ethylcelluloseis one that has an ethoxy content of 44 to 55%. Ethylcellulose may beused in the form of an alcoholic solution. In certain other embodiments,the hydrophobic material comprises polylactic acid, polyglycolic acid ora co-polymer of the polylactic and polyglycolic acid.

In certain embodiments, the hydrophobic material may comprise acellulose polymer selected from the group consisting of cellulose ether,cellulose ester, cellulose ester ether, and cellulose. The cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than zero and up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups present onthe anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials include apolymer selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di, and tricellulose alkanylates,moni, di, and tricellulose aroylates, and mono, di, and tricellulosealkenylates. Exemplary polymers cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2 to3 and an acetyl content of 35 to 44.8%.

More specific cellulosic polymers include cellulose propionate having aD.S. of 1.8 and a propyl content of 39.2 to 45 and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetylcontent of 13 to 15% and a butyryl content of 34 to 39%; celluloseacetate butyrate having an acetyl content of 2 to 29%, a butyryl contentof 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylatehaving a D.S. of 2.9 to 3 such as cellulose triacetate, cellulosetrivalerate, cellulose trilaurate, cellulose tripatmitate, cellulosetrisuccinate, and cellulose trioctanoate; cellulose diacylates having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulosesuch as cellulose acetate butyrate, cellulose acetate octanoate butyrateand cellulose acetate propionate.

Additional cellulose polymers useful for preparing an opioid antagonistin a substantially non-releasable form includes acetaldehyde dimethylcellulose acetate, cellulose acetate ethylcarbamate, cellulose acetatemethylcarbamate, and cellulose acetate dimethylaminocellulose acetate.

An acrylic polymer useful for preparation of the opioid antagonist in asubstantially non-releasable form includes, but are not limited to,acrylic resins comprising copolymers synthesized from acrylic andmethacrylic acid esters (e.g., the copolymer of acrylic acid lower alkylester and methacrylic acid lower alkyl ester) containing about 0.02 to0.03 mole of a tri (lower alkyl) ammonium group per mole of the acrylicand methacrylic monomers used. An example of a suitable acrylic resin isa polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit®RS trademark. Eudragit RS30D is preferred. Eudragit® RS is a waterinsoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) andtrimethylammoniumethyl methacrylate chloride (TAM) in which the molarratio of TAM to the remaining components (EA and MM) is 1:40. Acrylicresins such as Eudragit® RS may be used in the form of an aqueoussuspension.

In certain embodiments of the invention, the acrylic polymer may beselected from the group consisting of acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate co-polymers.

When the opioid antagonist in a substantially non-releasable formcomprises opioid antagonist particles coated with a coating that rendersthe antagonist substantially non-releasable, and when a cellulosepolymer or an acrylic polymer is used for preparation of the coatingcomposition, suitable plasticizers, e.g., acetyl triethyl citrate and/oracetyl tributyl citrate may also be admixed with the polymer. Thecoating may also contain additives such as coloring agents, talc and/ormagnesium stearate, which are well known in the coating art.

The coating composition may be applied onto the opioid antagonistparticles by spraying it onto the particles using any suitable sprayequipment known in the part. For example, a Wuster fluidized-bed systemmay be used in which an air jet, injected from underneath, fluidizes thecoated material and effects drying while the insoluble polymer coatingis sprayed on. The thickness of the coating will depend on thecharacteristics of the particular coating composition being used.However, it is well within the ability of one skilled in the art todetermine by routine experimentation the optimum thickness of aparticular coating required for a particular dosage form of the presentinvention.

The pharmaceutically acceptable hydrophobic material useful forpreparing an opioid antagonist in a substantially non-releasable formincludes a biodegradable polymer comprising a poly(lactic/glycolic acid)(“PLGA”), a polylactide, a polyglycolide, a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, polyesthers, polydioxanone, polygluconate,polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyphosphoesther or mixtures or blends of any of these.

In certain embodiments, biodegradable polymer comprises apoly(lactic/glycolic acid), a copolymer of lactic and glycolic acid,having molecular weight of about 2,000 to about 500,000 daltons. Theratio of lactic acid to glycolic acid is from about 100:0 to about25:75, with the ratio of lactic acid to glycolic acid of 65:35 beingpreferred.

Poly(lactic/glycolic acid) may be prepared by the procedure set forth inU.S. Pat. No. 4,293,539 (Ludwig et al.), the disclosure of which ishereby incorporated by reference in its entirety. In brief, Ludwigprepares the copolymer by condensation of lactic acid and glycolic acidin the presence of a readily removable polymerization catalyst (e.g., astrong acid ion-exchange resin such as Dowex HCR-W2-H). The amount ofcatalyst is not critical to the polymerization, but typically is fromabout 0.01 to about 20 parts by weight relative to the total weight ofcombined lactic acid and glycolic acid. The polymerization reaction maybe conducted without solvents at a temperature from about 10° C. toabout 25° C. for about 48 to about 96 hours, preferably under a reducedpressure to facilitate removal of water and by-products.Poly(lactic/glycolic acid) is then recovered by filtering the moltenreaction mixture in an organic solvent such as dichloromethane oracetone and then filtering to remove the catalyst.

Once the opioid antagonist in a substantially non-releasable form isprepared, it may be combined with an opioid agonist, along withconventional excipients known in the art, to prepare the oral dosageform of the present invention.

In certain preferred embodiments of the invention, the oral dosage formis a capsule or a tablet. When being formulated as a tablet, the opioidantagonist and agonist may be combined with one or more inert, non-toxicpharmaceutical excipients, which are suitable for the manufacture oftablets. Such excipients include, for example, an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate.

The oral dosage form of the present invention may be formulated toprovide immediate release of the opioid agonist contained therein. Inother embodiments of the invention, however, the oral dosage formprovides sustained-release of the opioid agonist.

In certain embodiments, the oral dosage forms providing sustainedrelease of the opioid agonist may be prepared by admixing the opioidantagonist in a substantially non-releasable form with the agonist anddesirable pharmaceutical excipients to provide a tablet, and thencoating the tablet with a sustained-release tablet coating.

In certain embodiments of the invention, sustained release opioidagonist tablets may be prepared by admixing the substantiallynon-releasable form of an opioid antagonist with an opioid antagonist ina matrix that provides the tablets with sustained-releasing properties.

Detailed description for preparing sustained-release oral dosage formsaccording to the present invention is set forth below.

Preparation of Controlled Release Dosage Forms Containing an OpioidAgonist and a Substantially Non-Releasable Form of an Opioid Antagonist

A combination of the opioid agonist and a substantially non-releasableform of an opioid antagonist may be formulated as a controlled orsustained release oral formulation in any suitable tablet, coated tabletor multiparticulate formulation known to those skilled in the art. Thesustained release dosage form may optionally include a sustained releasecarrier, which is incorporated into a matrix along with the opioidagonist and a non-available form of an opioid antagonist, or may beapplied as a sustained release coating.

In embodiments in which the opioid agonist comprises hydrocodone, thesustained release oral dosage forms may include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. In sustainedrelease oral dosage forms where hydromorphone is the therapeuticallyactive opioid, it is included in an amount from about 2 mg to about 64mg hydromorphone hydrochloride. In another embodiment, the opioidagonist comprises morphine, and the sustained release oral dosage formsof the present invention include from about 2.5 mg to about 800 mgmorphine, by weight. In yet another embodiment, the opioid agonistcomprises oxycodone and the sustained release oral dosage forms includefrom about 2.5 mg to about 800 mg oxycodone. In certain preferredembodiments, the sustained release oral dosage forms include from about20 mg to about 30 mg oxycodone. Controlled release oxycodoneformulations are known in the art. The following documents describevarious controlled release oxycodone formulations suitable for use inthe invention described herein, and processes for their manufacture:U.S. Pat. Nos. 5,266,331; 5,549,912; 5,508,042; and 5,656.295. Theopioid agonist may comprise tramadol and the sustained release oraldosage forms may include from about 25 mg to 800 mg tramadol per dosageunit. The dosage form may contain more than one opioid agonist toprovide a substantially equivalent therapeutic effect. Alternatively,the dosage form may contain molar equivalent amounts of other salts ofthe opioid agonists useful in the present invention.

In one preferred embodiment of the present invention, the sustainedrelease dosage form comprises such particles comprising the opioidagonist, wherein the particles have diameter from about 0.1 mm to about2.5 mm, preferably from about 0.5 mm to about 2 mm.

The opioid agonist particles are preferably film coated with a materialthat permits release of the opioid agonist at a sustained rate in anaqueous medium. The film coat is chosen so as to achieve, in combinationwith the other stated properties, a desired in-vitro release rate. Thesustained release coating formulations of the present invention shouldbe capable of producing a strong, continuous film that is smooth andelegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

The dosage forms comprising an opioid agonist and a substantiallynon-releasable opioid antagonist may optionally be coated with one ormore materials suitable for the regulation of the opioid agonist releaseor for the protection of the formulation. In one embodiment, coatingsare provided to permit either pH-dependent or pH-independent release,e.g., when exposed to gastrointestinal fluid. A pH-dependent coatingserves to release the opioid in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine, such that anabsorption profile is provided which is capable of providing at leastabout eight hours and preferably about twelve hours to up to abouttwenty-four hours of analgesia to a patient. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseof the opioid regardless of pH-changes in the environmental fluid, e.g.,the GI tract. It is also possible to formulate compositions, whichrelease a portion of the dose in one desired area of the GI tract, e.g.,the stomach, and release the remainder of the dose in another area ofthe GI tract, e.g., the small intestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the opioid analgesic (with or without theCOX-2 inhibitor) is coated with a hydrophobic material selected from (i)an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.The coating may be applied in the form of an organic or aqueous solutionor dispersion. The coating may be applied to obtain a weight gain fromabout 2 to about 25% of the substrate to obtain a desired sustainedrelease profile. Coatings derived from aqueous dispersions aredescribed, e.g., in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493,assigned to the Assignee of the present invention and herebyincorporated by reference.

Other examples of sustained release formulations and coatings which maybe used in accordance with the present invention include Assignee's U.S.Pat. Nos. 5,324,351; 5,156,467, and 5,472,712, hereby incorporated byreference in their entirety.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the controlled release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

To obtain a desirable dissolution profile, it may be necessary toincorporate two or more ammonio methacrylate copolymers having differingphysical properties, such as different molar ratios of the quaternaryammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparing,pH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Mini Tech, Inc.There are several different types of Eudragit®. For example, Eudragit® Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit® L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit® S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio to ultimately obtain a sustained releaseformulation having a desirable dissolution profile. Desirable sustainedrelease formulations may be obtained, for instance, from a retardantcoating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50%Eudragit® RS, and 10% Eudragit® RL: Eudragit® 90% RS. Of course, oneskilled in the art will recognize that other acrylic polymers may alsobe used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating, solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Processes for Preparing Coated Beads

When a hydrophobic controlled release coating material is used to coatinert pharmaceutical beads such as nu panel 18/20 beads, which arealready coated with an opioid agonist, a plurality of the resultantsolid controlled release beads may thereafter be placed in a gelatincapsule, with the opioid antagonist in a substantially non-releasableform. The dosage form provides an effective controlled release dose ofthe opioid agonist when ingested and contacted by an environmentalfluid, e.g., gastric fluid or dissolution media.

The controlled release head formulations of the present invention slowlyrelease the opioid agonist, e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The controlled release profile ofthe formulations of the invention can be altered, for example, byvarying the amount of overcoating with the hydrophobic material,altering the manner in which the plasticizer is added to the hydrophobicmaterial, by varying the amount of plasticizer relative to hydrophobicmaterial, by the inclusion of additional ingredients or excipients, byaltering the method of manufacture, etc. The dissolution profile of theultimate product may also be modified, for example, by increasing ordecreasing the thickness of the retardant coating.

Spheroids or beads coated with an opioid agonist may be prepared, e.g.,by dissolving the drug in water and then spraying the solution onto asubstrate, for example, nu panel 18/20 beads, using a Wuster insert.Optionally, additional ingredients are also added prior to coating thebeads to assist the binding of the opioid to the beads, and/or to colorthe solution, etc. For example, a product which includeshydroxypropylmethylcellulose, etc. with or without colorant (e.g.,Opadry®, commercially available from Colorcon. Inc.) may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the therapeutically active agent from the hydrophobiccontrolled release coating. An example of a suitable barrier agent isone which comprises hydroxypropylmethylcellulose. However, anyfilm-former known in the art may be used. It is preferred that thebarrier agent does not affect the dissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the therapeutically active agent by spraying using anysuitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid therapeutically active agent when the coated substrate is exposedto aqueous solutions, e.g. gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically activeagent, the manner of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic material, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, to substantially reduce agglomerationof the beads.

The release of the therapeutically active agent from the controlledrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of whichare hereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

Matrix Formulations

In other embodiments of the present invention, the controlled releaseformulation is achieved via a matrix having a controlled release coatingas set forth above. The present invention also comprisessustained-release tablets comprising an opioid agonist and opioidantagonist particles coated with a coating that renders the antagonistsubstantially non-releasable, wherein the agonist and the antagonist aredispersed in a controlled release matrix that affords in-vitrodissolution rates of the opioid agonist within the preferred ranges andthat releases the opioid agonist in a pH-dependent or pH-independentmanner. The materials suitable for inclusion in a controlled releasematrix will depend on the method used to form the matrix.

For example, a matrix in addition to the opioid agonist and thesubstantially non-releasable form of the coated opioid antagonist, mayinclude:

Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which is capable of impartingcontrolled release of the opioid may be used in accordance with thepresent invention.

Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

Of these polymers, acrylic polymers, especially Eudragit® RSPO—thecellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25 and 90° C. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of atleast one polyalkylene glycol.

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 30 to about 200° C., preferably from about 45° to about 90° C.Specifically, the hydrophobic material may comprise natural or syntheticwaxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl orpreferably cetostearyl alcohol), fatty acids, including but not limitedto fatty acid esters, fatty acid glycerides (mono-, di-, andglycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid,stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about30° to about 100° C.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25° and 90° C. are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

Preferably, a combination of two or more hydrophobic materials areincluded in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol. Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylene glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 20% and 50% (by wt) of the total dosage.

In one embodiment, the ratio of e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropyleneglycol or, which is preferred, polyethylene glycol. The number averagemolecular weight of the at least one polyalkylene glycol is preferredbetween 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a controlled release matrix mayalso contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Processes for Preparing Matrix-Based Beads

To facilitate the preparation of a solid, controlled release, oraldosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose and opioid or an opioid salt; (b) mixing the hydroxyalkylcellulose containing granules with at least one C₁₂-C₃₆ aliphaticalcohol; and (c) optionally, compressing and shaping the granules.Preferably, the granules are formed by wet granulating the hydroxyalkylcellulose/opioid with water. In a particularly preferred embodiment ofthis process, the amount of water added during the wet granulation stepis preferably between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as tow viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques, as long as the techniques used do not damagethe integrity of the substantially non-releasable form of the opioidantagonist added during the preparation of the matrix to the extent thatsufficient amount of the opioid antagonist becomes available to bereleased into the gastrointestinal system upon oral administration.Alternatively, the melt extrusion step may be performed with the opioidagonist to produce sustained release particles of the agonist, which maythen be combined with the substantially non-releasable form of theopioid antagonist. Generally, melt-granulation techniques involvemelting a normally solid hydrophobic material, e.g. a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g. ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598, assigned to the Assignee of the presentinvention and hereby incorporated by reference in its entirety.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. To achieveconstant release, the individual wax-like substances in the formulationshould be substantially iron-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic, together with at least one hydrophobic material andpreferably the additional hydrophobic material to obtain a homogeneousmixture. The homogeneous mixture is then heated to a temperaturesufficient to at least soften the mixture sufficiently to extrude thesame. The resulting homogeneous mixture is then extruded to formstrands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then blendedwith the opioid antagonist particles coated with a coating that rendersthe antagonist substantially non-releasable and divided into unit doses.The extrudate preferably has a diameter of from about 0.1 to about 5 mmand provides sustained release of the opioid agonist for a time periodof from about 8 to about 24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, a therapeutically active agent, and an optional binder;heating the homogenous mixture; extruding the homogenous mixture tothereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and combining the particles with the coated opioidantagonist particles and dividing them into unit doses. In this aspectof the invention, a relatively continuous manufacturing procedure isrealized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units;preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic material as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is combined with the coated opioid antagonistparticles and compressed into an oral tablet using conventionaltableting equipment using standard techniques. Techniques andcompositions for making tablets (compressed and molded), capsules (hardand soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the coated opioid antagonistparticles are added during the extrusion process and the extrudate canbe shaped into tablets as set forth in U.S. Pat. No. 4,957,681.(Klimesch, et al.), described in additional detail above and herebyincorporated by reference.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule can be further coated,with a sustained release coating such as the sustained release coatingsdescribed above. Such coatings preferably include a sufficient amount ofhydrophobic material to obtain a weight gain level from about 2 to about30 percent, although the overcoat may be greater depending upon thephysical properties of the particular opioid analgesic compound utilizedand the desired release rate, among other things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded multiparticulates containing oneor more of the therapeutically active agents disclosed above beforebeing encapsulated. Furthermore, the unit dosage forms can also includean amount of an immediate release opioid agonist for prompt therapeuticeffect. The immediate release opioid agonist may be incorporated, e.g.,as separate pellets within a gelatin capsule, or may be coated on thesurface of the multiparticulates after preparation of the dosage forms(e.g., controlled release coating or matrix-based). The unit dosageforms of the present invention may also contain a combination ofcontrolled release beads and matrix multiparticulates to achieve adesired effect.

The sustained release formulations of the present invention preferablyslowly release the opioid agonist, e.g., when ingested and exposed togastric fluids, and then to intestinal fluids. The sustained releaseprofile of the melt-extruded formulations of the invention can bealtered, for example, by varying the amount of retardant, i.e.,hydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the opioid agonist and/or coatedopioid antagonist particles, which are added thereafter to theextrudate. Such formulations typically will have the drugs blendedtogether with the extruded matrix material, and then the mixture wouldbe tableted to provide a slow release of the opioid agonist. Suchformulations may be advantageous, for example, when the therapeuticallyactive agent included in the formulation is sensitive to temperaturesneeded for softening the hydrophobic material and/or the retardantmaterial.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Example 1

In Example 1, a substantially non-releasable form of an opioidantagonist (naltrexone HCL) was prepared by coating naltrexone particleswith a coating that renders the antagonist substantially non-releasable.

Naltrexone HCl 2 mg Capsules (Formulation A)

Formula:

Amt/unit Amt/batch Ingredient (mg) (kg) Naltrexone HCl 2.0 0.04 EudragitRSPO 88.0 1.76 Stearyl Alcohol 15.0 0.3 Stearic Acid 15.0 0.3 ButylatedHydroxytoluene (BHT) 1.0 0.02 Size #2 Hard Gelatin Capsules N/A N/ATotal 121.0 2.42Process:

1. Milling Pass stearyl alcohol flakes through a mill. 2. Blending MixNaltrexone HCl, Eudragit, milled Stearyl Alcohol, Stearic Acid and BHTin a twin shell blender. 3. Extrusion Continuously feed the blendedmaterial into a twin screw extruder and collect the resultant strands ona conveyor. 4. Cooling Allow the strands to cool a Conveyor. 5.Pelletizing Cut the cooled strands into pellets using a Pelletizer. 6.Screening Screen the pellets and collect desired sieve portion. 7.Encapsulation Fill pellets into hard gelatin capsules at a target weightof 121 mgDissolution Method

-   1. Apparatus—USP Type II (Paddle), 75 rpm at 37° C.-   2. Sampling Time: 1, 2, 4, 8, 12, 24, 36-   3. Media: SGF for one hour/SIF thereafter-   4. Analytical Method: High Performance Liquid Chromatography    Results

Time (hour) 1 2 4 8 12 24 36 Mean % Dissolved 1.3 2.6 2.9 3.6 4.0 5.26.2Simulated Tampering ProcessNaltrexone Pellets were ground in a mortar and pestle to powder for thedissolution study.Dissolution Method: Same as aboveResults

Time (hour) 1 Mean % Dissolved 33.5

Example 2

In Example 2, a substantially non-releasable form of an opioidantagonist (naltrexone HCL) was prepared by coating naltrexone particleswith a coating that renders the antagonist substantially non-releasable.

Naltrexone HCl 2 mg Capsules (Formulation B)

Formula:

Amt/unit Amt/batch Ingredient (mg) (kg) Naltrexone HCl 2.0 0.04 EudragitRSPO 96.0 1.92 Stearyl Alcohol 22.0 0.44 Dibasic Calcium Phosphate 6.00.12 Butylated Hydroxytoluene 1.0 0.02 (BHT) Size #2 Hard Gelatin N/AN/A Capsules Total 127.0 2.54Process:

1. Milling Pass stearyl alcohol flakes through a mill. 2. Blending MixNaltrexone HCl, Eudragit, milled Stearyl Alcohol, Dibasic CalciumPhosphate and BHT in a twin shell blender. 3. Extrusion Continuouslyfeed the blended material into a twin screw extruder and collect theresultant strands on a conveyor. 4. Cooling Allow the strands to cool aConveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion. 7. Encapsulation Fill pellets into hard gelatin capsules at atarget weight of 127 mgDissolution Method

-   5. Apparatus—USP Type II (Paddle), 75 rpm at 37° C.-   6. Sampling Time: 1, 2, 4, 8, 12, 24, 36-   7. Media: SGF for one hour/SIF thereafter-   8. Analytical Method: High Performance Liquid Chromatography    Results

Time (hour) 1 2 4 8 12 24 36 Mean % Dissolved 3.1 5.9 8.9 12.2 14.7 19.924.6Simulated Tampering ProcessNaltrexone Pellets were ground in a mortar and pestle to powder for thedissolution study.Dissolution Method: Same as aboveResults

Time (hour) 1 Mean % Dissolved 36.4

Example 3 Immediate Release Naltrexone HCl 0.5 mg Tablets

Formula:

Amt/unit Amt/batch Ingredient (mg) (kg) Wet Granulation Naltrexone HCl0.5 0.1 Plasdone C-30 5.0 1.0 Avicel PH-102 58.0 11.6 Sterile Water forInjection 25.0* 5.0* Dry Mixing Avicel PH-102 58.0 11.6 Cab-O-Sil 0.30.06 Ac-Di-Sol 2.5 0.5 Magnesium Stearate 0.7 0.14 Total 125.0 25.0*Remains as residual moisture only. Not included in total weight.Process:

1. Solution Dissolve Naltrexone HCl and Plasdone in Sterile PreparationWater for Injection. 2. Wet Granulate Avicel PH-102 with solution asprepared in Granulation step 1. 3. Drying Dry granulated material fromstep 2 in a fluid bed dryer. 4. Milling Pass dried granulation through aComil 5. Mixing Mix milled granulation with remaining Avicel PH-102,Cab-O-Sil, Ac-Di-Sol, and Magnesium Stearate. 6. Compression Compressgranulation into tablets using a tablet press.Dissolution Method

-   9. Apparatus—USP Type II (Paddle), 50 rpm at 37° C.-   10. Sampling Time: 15, 30, and 60 minutes-   11. Media: 900 mL 0.1N HCl-   12. Analytical Method: High Performance Liquid Chromatography    Results

Time (minutes) 15 30 60 Mean % Dissolved 300 103 103

Example 4

This was an analytically blind, single dose, five treatments, 3-periodcrossover, pharmacokinetic study of two naltrexone pellet formulations(Formulation A and Formulation B) swallowed whole or after grindingcompared with an immediate-release naltrexone reference swallowed wholein normal healthy subjects. This study assessed the pharmacokinetic (PK)profiles of the two different formulations (Formulation A andFormulation B) of a single dose of one (1) pellet (each containing 2 mgof naltrexone) when ground then swallowed whole and five (5) pellets(each containing 2 mg of naltrexone) when swallowed whole. This studyalso compared the pharmacokinetics of each formulation administrationmethod to a single dose containing 1 mg of immediate release (IR)naltrexone when swallowed whole.

FIG. 1 shows the graphical representation of this study, which consistedof two groups (Group A and Group B) with 15 subjects in each group. Thetreatment order and treatments conditions were the same for each group,however, the test formulation for Group A was Formulation A and the testformulation for Group B was Formulation B. The groups were administeredthe one (1) pellet of one (1) mg IR naltrexone (NTX). Then after 7 days,the groups were administered one (1) pellet with two (2) mg of groundnaltrexone. Then after 7 more days, the groups were administered five(5) pellets with two (2) mg naltrexone per pellet.

After administration of the IR naltrexone, the ground naltrexone and theintact naltrexone, pharmacokinetic variables were assessed. Thesevariables included primary and secondary pharmacokinetic metrics. Theprimary pharmacokinetic metrics included (1) AUCt (area under the plasmaconcentration time course profile from dosing to last quantifiableconcentration; (2) AUC ∞ (area under the plasma concentration timecourse profile from dosing to infinity; and (3) Cmax (maximum observedplasma concentration). The secondary pharmacokinetic metrics included(1) tmax (time from dosing to maximum observed plasma concentration);(2) t½ (apparent terminal half-life); and (3) MRT (mean residence time).

The following tables show the pharmacokinetic data for the study ofExample 4. The data is given in both (1) data for one (1) rug IRnaltrexone, two (2) mg ground formulations of Formulation A or B, andten (10) mg intact formulations of Formulation A or B (“notdose-adjusted”), and (2) data that has been adjusted to correspond toone (1) me IR naltrexone, one (1) mg ground formulations of FormulationA or B, and one (1) mg intact formulations of Formulation A or B(“dose-adjusted”).

Table 1 shows the summary statistics of naltrexone over time.

Table 2 shows the not dose-adjusted summary statistics for thephamacokinetic metrics of naltrexone.

Table 3 shows the dose-adjusted summary statistics for thephamacokinetic metrics of naltrexone.

Table 4 shows the dose-adjusted summary statistics for thephamacokinetic metrics of naltrexone, where subject 11 is excluded.

Table 5 shows the not dose-adjusted statistical for the phamacokineticmetrics of naltrexone for Group A, Group B and Group A (excludingsubject 11).

Table 6 shows the dose-adjusted statistical for the phamacokineticmetrics of naltrexone for Group A, Group B and Group A (excludingsubject 11).

Table 7 shows the listing of pharmacokinetic metrics of naltrexone bysubject.

Table 8 shows the listing of plasma naltrexone concentration by subject.

Tables 1-8 are listed on pages 48a-48u.

TABLE 1 SUMMARY STATISTICS NALTREXONE CONCENTRATIONS OVER TIMEPopulation: ALL Subjects Valid for Safety Analysis GROUP A GROUP B 2 ×0.5 MG 2 MG 10 MG 2 × 0.5 MG 2 MG 10 MG HOUR IR GROUND(A) WHOLE(A) IRGROUND(B) WHOLE(B) At Dosing N 15 15 15 18 16 16 NEAN 0.51 24.80 1.020.57 3.57 4.45 SD 1.39 42.20 3.95 1.77 4.33 17.80 CV 272.66 170.14387.30 312.94 121.23 400.00 MIN 0.00 0.00 0.00 0.00 0.00 0.00 MAX 4.75157.00 15.30 7.00 13.30 71.20 0.5 hr   N 15 15 15 18 16 16 NEAN 133.1436.76 15.38 166.46 53.25 20.43 SD 75.00 25.32 13.20 150.23 63.41 20.27CV 56.33 70.53 85.86 90.25 119.07 99.22 MIN 52.20 6.26 2.94 45.40 4.570.00 MAX 323.00 82.50 52.80 656.00 264.00 69.50 1 hr N 15 15 15 18 16 16NEAN 149.38 70.90 42.06 142.81 106.57 44.22 SD 60.40 45.83 22.05 95.40102.38 38.82 CV 40.43 64.65 52.43 66.80 96.07 87.80 MIN 60.20 22.5015.40 65.20 40.00 10.30 MAX 244.00 183.00 78.50 464.00 443.00 175.00 2hrs N 15 15 15 18 16 16 NEAN 96.29 70.21 49.14 84.15 110.76 71.79 SD38.06 44.12 24.77 49.72 73.01 56.96 CV 39.53 62.83 50.42 59.09 65.9279.34 MIN 41.10 29.60 9.64 41.10 62.10 24.30 MAX 150.00 172.00 85.80250.00 356.00 270.00 3 hrs N 15 15 15 18 16 16 NEAN 66.58 59.32 49.8956.46 89.63 77.24 SD 24.68 32.79 24.18 38.43 57.11 59.88 CV 37.07 55.2748.46 68.07 63.71 77.52 MIN 21.70 25.30 19.90 26.40 35.60 25.80 MAX95.90 128.00 93.30 191.00 263.00 274.00 4 hrs N 15 14 15 18 16 16 NEAN43.32 74.34 45.59 36.94 74.91 66.11 SD 17.82 57.92 20.19 24.24 55.0444.63 CV 41.14 77.91 44.28 65.63 73.48 67.51 MIN 12.30 20.10 18.50 17.8029.80 23.80 MAX 67.50 214.00 77.20 121.00 223.00 193.00 6 hrs N 15 15 1518 16 16 NEAN 20.94 175.82 42.21 19.70 51.56 73.78 SD 9.83 514.84 20.8612.59 38.98 45.76 CV 46.92 292.82 49.41 63.91 75.59 62.02 MIN 9.29 18.8015.60 9.37 15.30 26.40 MAX 38.80 2035.00 83.60 58.30 163.00 179.00 12hrs  N 15 15 15 18 16 16 NEAN 7.38 19.90 26.15 7.00 36.28 130.90 SD 3.3213.66 13.33 5.79 18.85 83.52 CV 45.04 68.65 51.00 82.70 51.94 63.81 MIN2.65 5.82 11.70 2.74 15.00 37.10 MAX 14.70 61.60 58.60 26.20 77.30302.00 18 hrs  N 14 14 15 18 16 16 NEAN 8.86 13.16 18.74 2.94 17.69112.42 SD 12.98 10.19 7.75 2.66 9.72 65.54 CV 146.45 77.46 41.36 90.5054.96 58.30 MIN 0.00 6.30 7.32 0.00 6.77 24.90 MAX 52.60 45.80 36.4010.50 39.70 234.00 24 hrs  N 15 15 15 18 16 16 NEAN 4.00 8.44 12.69 2.0921.49 95.75 SD 4.93 6.60 4.57 2.75 35.18 74.01 CV 123.30 78.12 36.03131.71 163.68 77.30 MIN 0.00 2.66 6.64 0.00 5.73 21.50 MAX 18.60 28.7021.00 10.00 150.00 321.00 30 hrs  N 14 15 15 18 16 16 NEAN 2.78 13.4021.52 1.20 9.60 99.24 SD 3.60 17.79 10.99 1.91 4.98 74.66 CV 129.80132.73 51.09 158.76 51.88 75.23 MIN 0.00 3.36 7.98 0.00 4.26 38.10 MAX10.50 73.80 45.10 6.29 22.50 335.00 36 hrs  N 15 15 15 18 16 16 NEAN1.22 8.24 16.85 1.52 18.80 64.43 SD 2.33 6.86 12.47 2.97 46.11 43.17 CV191.54 83.27 73.98 195.54 245.33 67.01 MIN 0.00 2.35 4.17 0.00 2.9430.00 MAX 7.71 24.50 57.70 12.40 191.00 193.00

TABLE 2 SUMMARY STATISTICS FOR PHARMACOKINETIC METRICS - NOTDOSE-ADJUSTED Population. Valid for PK Analysis NALTREXONE GROUP A GROUPB 2 MG 10 MG 2 MG 10 MG PK PARAMETER STATISTICS 2 × 0.5 MG IR GROUND (A)WHOLE (A) 2 × 0.5 MG IR GROUND (B) WHOLE (B) AUC (0-T) N 15 15 15 18 1616 MEAN 622.35 1379.41 900.84 543.61 1193.21 3410.98 SD 227.47 2099.31299.27 388.16 768.70 2082.54 CV 36.55 152.19 33.22 71.40 64.42 61.05 MIN204.26 334.65 618.01 239.66 501.45 1112.17 MAX 941.35 8777.40 1686.081859.42 3589.49 9326.50 AUC (INF) N 5 1 2 9 8 3 MEAN 624.64 1401.851163.88 679.17 1198.77 5278.41 SD 302.91 — 17.57 495.67 497.94 1536.68CV 48.49 — 1.51 72.98 41.54 29.11 MIN 217.79 1401.85 1151.45 258.46543.95 3525.82 MAX 925.07 1401.85 1176.30 1894.32 1934.31 6394.97 CMAX N15 15 15 18 16 16 MEAN 164.73 231.40 57.93 176.53 128.94 141.57 SD 72.41502.25 20.68 145.59 95.58 86.47 CV 43.96 217.05 35.70 82.47 74.13 61.08MIN 65.50 37.00 33.40 71.30 62.10 44.80 MAX 323.00 2035.00 93.30 656.00443.00 335.00 TMAX N 15 15 15 18 16 16 MEAN 0.83 2.53 8.53 0.72 3.3818.75 SD 0.24 1.96 11.22 0.26 5.54 7.86 CV 29.28 77.33 131.53 35.40164.04 41.93 MIN 0.50 0.00 1.00 0.50 1.00 12.00 MAX 1.00 6.00 30.00 1.0024.00 30.00 TERMINAL N 5 2 2 9 9 5 HALF-LIFE MEAN 7.27 41.79 8.19 8.9213.77 20.02 SD 4.20 47.87 1.03 5.59 6.23 22.88 CV 57.81 114.55 12.6162.74 45.27 114.31 MIN 3.54 7.94 7.46 3.27 6.87 6.11 MAX 13.99 75.648.92 21.15 26.10 60.33 SUMMARY STATISTICS FOR PHARMACOKINETIC METRICS -NOT DOSE-ADJUSTED RECORD WITH SUBJECT = 11 AND TYPE = NALTREXONE WASEXCLUDED Population. Valid for PK Analysis NALTREXONE GROUP A GROUP B 2MG 10 MG 2 MG 10 MG PK PARAMETER STATISTICS 2 × 0.5 MG IR GROUND (A)WHOLE (A) 2 × 0.5 MG IR GROUND (B) WHOLE (B) AUC (0-T) N 14 14 14 18 1616 MEAN 611.43 850.98 886.30 543.81 1193.21 3410.98 SD 231.95 485.15305.02 388.16 768.70 2082.54 CV 37.94 57.01 34.42 71.40 64.42 61.05 MIN204.26 334.65 618.01 239.66 501.45 1112.17 MAX 941.35 2052.25 1686.081859.42 3589.49 9326.50 AUC (INF) N 5 1 1 9 8 3 MEAN 624.64 1401.851151.45 679.17 1198.77 5278.41 SD 302.91 — — 495.67 497.94 1536.68 CV48.49 — — 72.98 41.54 29.11 MIN 217.79 1401.85 1151.45 258.46 543.953525.82 MAX 925.07 1401.85 1151.45 1894.32 1934.31 6394.97 CMAX N 14 1414 18 16 16 MEAN 153.43 102.57 55.41 176.53 128.94 141.57 SD 59.85 59.6618.91 145.59 95.58 86.47 CV 39.01 58.16 34.13 82.47 74.13 61.08 MIN65.50 37.00 33.40 71.30 62.10 44.80 MAX 244.00 214.00 83.60 656.00443.00 335.00 TMAX N 14 14 14 18 16 16 MEAN 0.86 2.29 8.93 0.72 3.3818.75 SD 0.23 1.77 11.54 0.26 5.54 7.86 CV 27.35 77.56 129.24 35.40164.04 41.93 MIN 0.50 0.00 1.00 0.50 1.00 12.00 MAX 1.00 6.00 30.00 1.0024.00 30.00 TERMINAL N 5 2 1 9 9 5 HALF-LIFE MEAN 7.27 41.79 8.92 8.9213.77 20.02 SD 4.20 47.87 — 5.59 6.23 22.88 CV 57.81 114.55 — 62.7445.27 114.31 MIN 3.54 7.94 8.92 3.27 6.87 6.11 MAX 13.99 75.64 8.9221.15 26.10 60.33

TABLE 3 SUMMARY STATISTICS FOR NALTREXONE PHARMACOKINETIC METRICS -DOSE-ADJUSTED Population: Valid for PK Analysis NALTREXONE GROUP A GROUPB 2 MG 10 MG 2 MG 10 MG PK PARAMETER STATISTICS 2 × 0.5 MG IR GROUND (A)WHOLE (A) 2 × 0.5 MG IR GROUND (B) WHOLE (B) AUC (0-T) N 15 15 15 18 1616 MEAN 622.35 689.70 90.08 543.61 596.60 341.10 SD 227.47 1049.66 29.93388.16 384.35 208.25 CV 36.55 152.19 33.22 71.40 64.42 61.05 MIN 204.26167.33 61.80 239.66 250.73 111.22 MAX 941.35 4388.70 168.61 1859.421794.75 932.65 AUC (INF) N 5 1 2 9 8 3 MEAN 624.64 700.93 116.39 679.17599.38 527.84 SD 302.91 — 1.76 495.67 248.97 153.67 CV 48.49 — 1.5172.98 41.54 29.11 MIN 217.79 700.93 115.15 258.46 271.98 352.58 max925.07 700.93 117.63 1894.32 967.16 639.50 CMAX N 15 15 15 18 16 16 MEAN164.73 115.70 5.79 176.53 64.47 14.16 SD 72.41 251.13 2.07 145.59 47.798.65 CV 43.96 217.05 35.70 82.47 74.13 61.08 MIN 65.50 18.50 3.34 71.3031.05 4.48 MAX 323.00 1017.50 9.33 656.00 221.50 33.50 FREL N 0 15 15 015 16 MEAN — 102.87 15.74 — 122.27 65.44 SD — 130.10 5.73 — 67.46 19.57CV — 126.46 36.41 — 55.17 29.91 MIN — 33.52 8.98 — 77.89 41.28 MAX —566.18 31.39 — 359.29 104.06 CMAX (GROUND)/ N 0 15 0 0 15 0 CMAX (WHOLE)MEAN — 15.98 — — 4.97 — SD — 26.22 — — 2.38 — CV — 164.09 — — 47.91 —MIN — 4.32 — — 2.55 — MAX — 109.06 — — 10.68 —

TABLE 4 SUMMARY STATISTICS FOR NALTREXONE PHARMACOKINETIC MATRICS -DOSE-ADJUSTED RECORD WITH SUBJECT = 11 AND TYPE - NALTREXONE WASEXCLUDED Population: Valid for PK Analysis NALTREXONE GROUP A GROUP B 2MG 10 MG 2 MG 10 MG PK PARAMETER STATISTICS 2x0 5 MG IR GROUND (A) WHOLE(A) 2x0.5 MG IR GROUND (B) WHOLE (B) AUC (0-τ) N  14  14  14  18  16  16MEAN 611.43  425.49  88.63  543.61  596.60 341.10 SD 231.95  262.58 30.50  388.18  354.35 208.25 CV  37.94  57.01  34.42  71.40  64 42  6105 MIN 204.26  157.33  61.80  215.66  250.73 111 22 MAX 941.35 1026.13168.61 1859.42 1794.75 932.65 AUC (INF) N  5   1  1   9   8  3 MEAN624.64  700 93 115 15  679.17  599.38 527.64 SD 307.91 — —  495.67 248.97 153 67 CV  48.49 — —  72.89  41.54  29 11 MIN 217.79  700.93115.15  258.46  271.98 353 58 MAX 925.07  700.93 115.25 1894.32  967.16639 50 CMAX N  14  14  14  18  16  16 MEAN 151.43  51.29  5 54  176.53 64 47  14 16 SD  59.85  29.83  1.89  145.59  47.79  8.65 CV  33.01  5816  34.13  82.47  74.13  61 08 MIN  65 50  18 50  3 34  71.20  31.05  418 MAX 244.00  107 00  8.36  636.00  221.50  33 50 FREL N  0  14  14   0 15  16 MEAN —  69.78  15 85 —  123.27  65.14 SD —  23.14  5.93 —  67.46 19 57 CV —  33.16  37.44 —  55.17  29 91 MIN —  13.32  8.49 —  77.89 41.26 MAX —  109.22  31.39 —  359.29 304.06 CMAX (GROUND)/ N  0  14  0  0  15  0 CMAX (WHOLE) MEAN —   9.32 — —   4 97 — SD —   5.16 — —  2.38 — CV —  35.25 — —  47.91 — MIN —   4.12 — —   2 55 — MAX —  21.63— —  10.68 —

TABLE 5 STATISTICAL ANALYSIS OF PHARMACOKINETIC METRICS - NOTDOSE-ADJUSTED Population: Valid for PK Analysis NALTREXONE GEOMETRIC 90%CI P-VALUE PK PARAMETER TREATMENT N LS MEAN COMPARISON RATIO LOWER UPPERRATIO = 1 GROUP A AUC (0-τ) 2X0.5 MG 15  576.48 2 mg GROUND (A) VS.2X0.5 MG 1.53 1.19 1 96 0 01 2 mg GROUND (A) 15  180.03 2 mg GROUND (A)VS. 10 mg WHOLE (A) 1.02 0.75 1 31 0.89 10 mg. WHOLE (A) 15  161.94 10mg. WHOLE (A) VS. 2X0 5 MG 1.50 1.16 1 92 0 01 AUC (INF) 2X0.2 MG 5 —Not Analyzed — — — — 2 mg. GROUND (A) 1 — Not Analyzed — — — — 10 mg.WHOLE (A) 2 — Not Analyzed — — — — CMAX 2X0.5 MG 15  150.03 2 mg GROUND(A) VS. 2X0.5 MG 0.71 0 53 0 95 0 05 2 mg GROUND (A) 15  106 53 2 mg.GROUND (A) VS 10 mg. WHOLE (A) 1.95 1 46 2.61 0 00 10 mg. WHOLE (A) 15 54 54 10 mg. WHOLE (A) VS 2X0.5 MG 0.36 0.27 0 48 0 00 GROUP B AUC(0-τ) 2X0 5 MG 18  459.47 2 mg GROUND (B) VS. 2X0.5 MG 2.28 1.98 2.630.00 2 mg GROUND (B) 16 1048.00 2 mg. GROUND (B) VS. 10 mg. WHOLE (B)0.16 0.11 0 42 0 00 10 mg. WHOLE (B) 16 2916.31 10 mg. WHOLE (B) VS.2X0.5 MG 6 35 3.50 7.32 0.00 AUC (INF) 2X0.5 MG 9 — Not Analyzed — — — —2 mg. GROUND (B) 8 — Not Analyzed — — — — 10 mg. WHOLE (B) 1 — NotAnalyzed — — — — CMAX 2X0.5 MG 15  142.73 2 mg. GROUND (B) VS. 2X0.5 MG0.77 0 65 0.91 0 01 2 mg GROUND (B) 16  110 35 2 mg. GROUND (B) VS. 10mg. WHOLE (B) 0.93 0.78 1.10 0 45 10 mg. WHOLE (B) 16  119.14 10 mg.WHOLE (B) VS. 2X0 5 MG 0.83 0.71 0.99 0 07 STATISTICAL ANALYSIS OFPHARMACOKINETIC METRICS - NOT DOSE-ADJUSTED RECORD WITH SUBJECT = 11 ANDTYPE - NALTREXONE WAS EXCLUDED Population: Valid for PK AnalysisNALTREXONE GROUP A GEOMETRIC 90% CI P-VALUE PK PARAMETER TREATMENT N LSMEAN COMPARISON RATIO LOWER UPPER RATIO = 1 AUC (0-τ) 2X0.5 MG 14 564 412 mg. GROUND (A) VS. 2X0.5 MG 1 32 1.13 1 33 0 01 2 mg. GROUND (A) 14746.76 2 mg. GROUND (A) VS 10 mg WHOLE (A) 0.88 0.75 1 04 0.19 10 mgWHOLE (A) 14 846.12 10 mg. WHOLE (A) VS 2X0.5 MG 1.50 1 28 1.75 0 00 AUC(INF) 2X0.5 MG 5 — Not Analyzed — — — — 2 mg GROUND (A) 1 — Not Analyzed— — — — 10 mg. WHOLE (A) 1 — Not Analyzed — — — — CMAX 2X0.5 MG 14142.09 2 mg. GROUND (A) VS 2X0 5 MG 0.61 0 50 0 73 0.00 2 mg GROUND (A)14  86.29 2 mg GROUND (A) VS 10 mg WHOLE (A) 1.64 1.36 1.99 0.00 10 mgWHOLE (A) 14  52 49 10 mg. WHOLE (A) VS 2X0 5 MG 0.37 0.31 0.45 0.00

TABLE 6 STATISTICAL ANALYSIS OF NALTREXONE PHARMACOKINETIC METRICS -DOSE-ADJUSTED Population: Valid for PK Analysis NALTREXONE GEOMETRIC 90%CI P-VALUE PK PARAMETER TREATMENT N LS MEAN COMPARISON RATIO LOWER UPPERRATIO = 1 GROUP A AUC (0-T) 2 × 0.5 MG 15 576.48 2 mg GROUND (A) 0.760.59 0.98 0.08 VS. 2 × 0.5 MG 2 mg. GROUND (A) 15 440.04 2 mg. GROUND(A) 5.11 3.97 6.56 0.00 VS. 10 mg WHOLE (A) 10 mg WHOLE (A) 15 86.19 10mg. WHOLE (A) 0.15 0.12 0.19 0.00 VS. 2 × 0.5 MG AUC (INF) 2 × 0.5 MG 5— Not Analyzed — — — — 2 mg GROUND (A) 1 — Not Analyzed — — — — 10 mgWHOLE (A) 2 — Not Analyzed — — — — CMAX 2 × 0.5 MG 15 150.09 2 mg.GROUND (A) 0.35 0.27 0.47 0.00 VS. 2 × 0.5 MG 2 mg GROUND (A) 15 53.26 2mg GROUND (A) 9.77 7.32 13.03 0.00 VS. 10 mg. WHOLE (A) 10 mg WHOLE (A)15 5.45 10 mg. WHOLE (A) 0.04 0.03 0.05 0.00 VS. 2 × 0.5 MG GROUP B AUC(0-T) 2 × 0.5 MG 18 459.47 2 mg GROUND (B) 1.14 0.99 1.32 0.13 VS. 2 ×0.5 MG 2 mg GROUND (B) 16 524.00 2 mg GROUND (B) 1.80 1.55 2.08 0.00 VS.10 mg WHOLE (B) 10 mg. WHOLE (B) 16 291.63 10 mg. WHOLE (B) 0.63 0.550.73 0.00 VS. 2 × 0.5 MG AUC (INF) 2 × 0.5 MG 9 — Not Analyzed — — — — 2mg. GROUND (B) 8 — Not Analyzed — — — — 10 mg WHOLE (B) 3 — Not Analyzed— — — — CMAX 2 × 0.5 MG 18 142.73 2 mg GROUND (B) 0.39 0.33 0.46 0.00VS. 2 × 0.5 MG 2 mg. GROUND (B) 16 55.17 2 mg GROUND (B) 4.63 3.91 5.490.00 VS. 10 mg WHOLE (B) 10 mg. WHOLE (B) 16 11.51 10 mg WHOLE (B) 0.080.07 0.10 0.00 VS. 2 × 0.5 MG STATISTICAL ANALYSIS OF NALTREXONEPHARMACOKINETIC METRICS - DOSE-ADJUSTED RECORD WITH SUBJECT = 11 ANDTYPE = NALTREXONE WAS EXCLUDED Population: Valid for PK AnalysisNALTREXONE GEOMETRIC 90% CI P-VALUE PK PARAMETER TREATMENT N LS MEANCOMPARISON RATIO LOWER UPPER RATIO = 1 GROUP A AUC (0-T) 2 × 0.5 MG 14564.41 2 mg GROUND (A) 0.66 0.56 0.78 0.00 VS. 2 × 0.5 MG 2 mg. GROUND(A) 14 373.38 2 mg. GROUND (A) 4.41 3.75 5.18 0.00 VS. 10 mg. WHOLE (A)10 mg. WHOLE (A) 14 84.68 10 mg. WHOLE (A) 0.15 0.13 0.18 0.00 VS. 2 ×0.5 MG AUC (INF) 2 × 0.5 MG 5 — Not Analyzed — — — — 2 mg GROUND (A) 1 —Not Analyzed — — — — 10 mg. WHOLE (A) 1 — Not Analyzed — — — — CMAX 2 ×0.5 MG 14 142.09 2 mg GROUND (A) 0.30 0.25 0.37 0.00 VS. 2 × 0.5 MG 2mg. GROUND (A) 14 43.14 2 mg GROUND (A) 8.22 6.80 9.93 0.00 VS. 10 mgWHOLE (A) 10 mg. WHOLE (A) 14 5.25 10 mg. WHOLE (A) 0.04 0.03 0.04 0.00VS. 2 × 0.5 MG

TABLE 7 LISTING OF PHARMACOKINETIC METRICS BY SUBJECT Population: Validfor PK Analysis ANALYTE: NALTREXONE TERMINAL SUBJECT AUC (0-T) AUC (INF)TMAX CMAX HALF-LIFE TREATMENT NUMBER VISIT (pg*h/ml) (pg*h/ml) (hour)(pg/ml) (hour) GROUP A 2 × 0.5 MG 1 Visit 1 935.15 — 1.0 244.0 — 2 Visit1 607.92 — 1.0 195.0 — 3 Visit 1 898.13 925.07 1.0 237.0 5.20 4 Visit 1366.00 — 1.0 101.0 — 5 Visit 1 941.35 — 1.0 216.0 — 6 Visit 1 382.37397.75 1.0 102.0 4.96 7 Visit 1 670.50 — 0.5 203.0 — 8 Visit 1 685.11745.47 1.0 150.0 13.99 9 Visit 1 665.53 — 1.0 99.2 — 10 Visit 1 562.93 —0.5 104.0 — 11 Visit 1 775.14 — 0.5 323.0 — 12 Visit 1 204.26 217.79 0.565.5 3.54 13 visit 1 802.11 837.14 1.0 191.0 8.64 14 Visit 1 435.03 —1.0 96.3 — 15 Visit 1 403.26 — 0.5 144.0 — 2 mg GROUND (A) 1 Visit 2806.40 — 1.0 112.0 — 2 Visit 2 788.02 — 4.0 150.0 — 3 Visit 2 1371.051401.85 1.0 183.0 7.94 4 Visit 2 586.50 — 0.0 157.0 — 5 Visit 2 2052.25— 2.0 129.0 — 6 Visit 2 441.69 — 2.0 48.5 — 7 Visit 2 1464.67 — 4.0214.0 — 8 Visit 2 710.94 — 1.0 71.9 75.64 9 Visit 2 446.40 — 1.0 49.5 —10 Visit 2 542.77 — 1.0 45.0 — 11 Visit 2 8777.40 — 6.0 2035.0 — 12Visit 2 334.65 — 1.0 39.0 — 13 Visit 2 1101.80 — 4.0 139.0 — 14 Visit 2524.32 — 6.0 37.0 — 15 Visit 2 742.28 — 4.0 61.1 — 10 mg. WHOLE (A) 1Visit 3 839.50 — 3.0 56.4 — 2 Visit 3 755.13 — 2.0 48.9 — 3 Visit 31097.82 1151.45 2.0 83.4 8.92 4 Visit 3 618.01 — 30.0 36.3 — 5 Visit 31302.65 — 6.0 76.7 — 6 Visit 3 902.25 — 3.0 52.2 — 7 Visit 3 865.55 —2.0 67.0 — 8 Visit 3 1008.33 — 1.0 78.5 — 9 Visit 3 694.48 — 2.0 35.2 —10 Visit 3 693.64 — 6.0 43.1 — 11 Visit 3 1104.30 1176.30 3.0 93.3 7.4612 Visit 3 641.24 — 30.0 45.1 — 13 Visit 3 1686.08 — 6.0 83.6 — 14 Visit3 672.55 — 30.0 35.9 — 15 Visit 3 631.01 — 2.0 33.4 — GROUP B 2 × 0.5 MG16 Visit 1 428.16 446.42 1.0 109.0 4.18 17 Visit 1 257.35 — 1.0 85.1 —18 Visit 1 453.35 — 0.5 161.0 — 19 Visit 1 311.44 — 1.0 71.3 — 20 Visit1 239.66 — 0.5 80.3 — 21 Visit 1 647.69 692.12 1.0 167.0 13.22 22 Visit1 782.92 850.05 0.5 249.0 21.15 23 Visit 1 266.05 — 1.0 83.3 — 24 Visit1 352.40 395.80 0.5 173.0 8.43 25 Visit 1 699.02 741.39 0.5 244.0 10.8826 Visit 1 449.97 474.86 0.5 137.0 6.99 27 Visit 1 1859.42 1894.32 0.5656.0 7.42 28 Visit 1 595.61 — 1.0 169.0 — 29 Visit 1 243.17 258.46 0.572.6 3.27 30 Visit 1 257.82 — 1.0 72.0 — 118 Visit 3 341.18 359.10 0.5107.0 4.70 119 Visit 2 703.29 — 1.0 143.0 — 219 Visit 3 896.55 — 0.5398.0 — 2 mg. GROUND (B) 16 Visit 2 944.40 — 2.0 130.0 — 17 Visit 2633.29 — 2.0 65.4 — 19 Visit 2 996.09 — 2.0 97.2 — 20 Visit 2 501.45543.95 2.0 62.1 10.02 21 Visit 2 1150.47 — 3.0 81.4 — 22 Visit 2 1672.311735.22 2.0 153.0 6.87 23 Visit 2 665.53 — 2.0 86.2 — 24 Visit 2 642.95723.46 1.0 82.4 11.44 25 Visit 2 1373.01 1543.76 3.0 156.0 11.38 26Visit 2 700.93 864.85 2.0 64.1 17.56 27 Visit 2 3589.49 — 1.0 443.0 — 28Visit 2 1071.94 1192.53 2.0 126.0 11.64 29 Visit 2 1747.36 — 24.0 150.0— 30 Visit 2 693.62 — 3.0 69.1 26.10 118 Visit 1 845.31 1052.04 2.0 70.120.21 219 Visit 1 1863.14 1934.31 1.0 227.0 8.71 10 mg WHOLE (B) 16Visit 3 3143.15 — 30.0 117.0 — 17 Visit 3 2677.88 — 12.0 118.0 — 20Visit 3 1864.16 — 12.0 79.8 — 21 Visit 3 3385.73 — 24.0 132.0 60.33 22Visit 3 5899.39 6394.97 12.0 300.0 7.92 23 Visit 3 1112.17 — 30.0 44.8 —24 Visit 3 1996.78 — 12.0 85.5 — 25 Visit 3 3261.30 3525.82 12.0 149.06.11 26 Visit 3 2153.12 — 30.0 86.2 — 27 Visit 3 9326.50 — 30.0 335.0 —28 Visit 3 5348.95 — 18.0 202.0 — 29 Visit 3 1985.45 — 12.0 70.2 — 30Visit 3 2364.90 — 18.0 91.5 — 118 Visit 2 2030.11 — 24.0 74.1 16.60 119Visit 1 2901.13 — 12.0 125.0 — 219 Visit 2 5122.88 5914.43 12.0 255.09.14

TABLE 8 LISTING OF PLASMA NALTREXONE CONCENTRATIONS BY SUBJECTPopulation: ALL Subjects Valid for Safety Analysis SUBJECT AT 0.5 1 2 34 6 12 18 24 30 36 TREATMENT NUMBER VISIT DOSING HR HR HRS HRS HRS HRSHRS HRS HRS HRS HRS GROUP A 2 × 0.5 MG 1 1 0 159 244 150 95.9 67.5 24.98.97 11.4 5.31 10.5 2.94 2 1 0 52.2 195 128 85.7 52.4 17.9 6.39 3.334.45 0 0 3 1 0 202 237 135 93.8 65.9 38.8 14.7 6.26 3.59 0 0 4 1 0 66.6101 68.7 47.6 28.3 10.9 5.32 2.74 2.08 0 5 1 4.75 201 216 148 93.7 63.131.2 11.1 6.9 4.62 9.61 7.71 6 1 2.9 86.3 102 71.5 65.2 28.6 11.5 4.992.15 0 0 0 7 1 0 203 149 109 81.8 53.9 24.2 8.15 4.33 0 0 4.64 8 1 0 104150 94.8 78.5 44.8 26.7 10 7.5 5.47 4.42 2.99 9 1 0 66.4 99.2 60.3 40.834.2 13.2 4.99 52.6 2.53 0 0 10 1 0 104 87 52.9 52.5 30.4 15.2 7.36 10.518.6 5.04 0 11 1 0 323 203 127 82.2 57.8 28.3 5.31 6.81 0 0 0 12 1 065.5 60.2 41.1 21.7 12.3 9.29 2.65 0 0 0 0 13 1 0 147 191 132 83.9 59.336.7 11.3 6.27 3.31 2.81 0 14 1 0 73.1 96.3 66.8 36.7 28.8 12.9 3.24 102.93 0 15 1 0 144 110 59.3 38.7 22.5 12.4 6.2 3.26 0 3.55 0 2 mg. 1 231.8 53.9 112 68.9 60.9 63.1 41.4 16.8 13.7 6.68 8.74 7.31 GROUND (A) 22 7.62 17.5 22.9 50 34 150 27.6 18.3 8.46 11.2 10.9 3 2 21.3 82.5 183172 115 85.9 32.8 19 7.67 5.63 2.69 4 2 157 6.26 31.9 33.2 87.7 36.431.4 12.1 8.42 3.07 9.02 7.81 5 2 80.4 67.8 127 129 128 118 104 61.645.8 28.7 28 22.8 6 2 0 14.7 33.2 48.5 44.4 38.7 27.1 9.67 7.05 2.664.46 2.35 7 2 0 56.4 86.1 96.6 88.4 214 41.4 20.7 11.8 7.82 73.8 5.19 82 15.4 56.6 71.9 67.1 51.1 52.5 36.8 14.9 14.1 7.49 6.94 6.71 9 2 27.221.4 49.5 29.6 27.7 35.2 28.2 11.2 7.53 3.35 4.49 3.15 10 2 0 15.2 4535.5 28 30.4 27.1 14.7 10.8 16.7 3.36 3.52 11 2 0 77.8 107 130 65.9 50.82035 15.4 8.82 6.61 8.26 3.87 12 2 0 20.8 39 29.8 25.3 20.1 18.8 5.826.3 4.51 3.68 4.23 13 2 10.5 23.9 87.9 87.5 66.1 139 46 32.2 16.6 9.3515.2 11.7 14 2 0 19.9 34.1 36.1 26.5 31.4 37 14.9 6.31 4.31 9.57 6.85 152 20.8 16.6 33 39.4 40.8 61.1 49.6 17.4 8 9.29 8.69 24.5 10 mg. 1 3 016.7 30.8 42.2 56.4 55.3 36.7 19.4 22.6 10.1 18.7 18.3 WHOLE (A) 2 3 013.2 44.9 48.9 44.8 40.7 26.1 19.5 15.7 18.5 15.8 12.9 3 3 0 5.75 57.883.4 80.6 77.2 69.4 37.9 23.8 10.6 7.98 4.17 4 3 0 3.57 15.7 22.3 19.918.5 16.7 11.7 9.21 8.64 36.3 24.2 5 3 15.3 13.5 59.9 71.3 70.6 70.376.7 48.5 23.9 14 18.5 21.2 6 3 0 19.6 34.6 48.3 52.2 43.4 51.7 21.323.7 15 14.7 15.3 7 3 0 21.4 54.2 67 60.7 55 38.2 22.8 14.4 13.5 16.5 168 3 0 31.2 78.5 72 71.4 48.1 37.9 31.2 25.9 14.8 15.5 14.1 9 3 0 12 2635.2 20.3 31.1 24.7 15.1 17.7 11.4 30.3 7.01 10 3 0 2.94 28.8 18.7 33.426.9 43.1 27.3 13.8 9.47 10.4 13.3 11 3 0 52.8 71.1 85.8 93.3 73.2 51.728.9 22.9 20.4 12.6 6.69 12 3 0 4.61 16.9 26.6 23.6 25 15.6 12.5 7.326.64 45.1 15.6 13 3 0 21 72.5 72.3 68.8 68.8 83.6 58.6 36.4 21 28.9 57.714 3 0 3.97 23.8 9.64 20.9 21.7 29.4 16.2 11.3 8.02 35.9 14.5 15 3 08.39 15.4 33.4 31.5 28.6 31.6 21.3 12.5 8.21 15.6 11.8 GROUP B 2 × 0.5MG 16 1 0 108 109 73 43.7 31.4 22.2 5.12 3.03 0 0 0 17 1 0 62.9 85.147.7 33.7 20.2 9.39 4.27 0 0 0 0 18 1 0 161 124 68.7 40.3 27.7 11.7 3.742.78 2.13 4.06 2.03 19 1 0 45.4 71.3 50.6 37.2 24.5 11.8 3.84 2.4 0 3.042.61 20 1 0 80.3 65.2 41.1 29.4 22 9.37 3.21 0 0 0 0 21 1 0 118 167 11469.2 41.5 21.7 8.43 5.31 3.97 2.99 2.33 22 1 0 249 216 122 77.3 44.221.9 11.4 5.48 3.26 2.63 2.2 23 1 0 62.8 83.3 54.3 34.6 23 10.1 2.79 0 00 0 24 1 0 173 105 48.4 31.1 20.8 9.58 4.57 3.57 0 0 0 25 1 0 244 198109 60 47.6 31.4 5.8 3.27 2.7 0 0 26 1 0 137 122 76.7 52.8 36.6 16.25.56 0 2.47 0 0 27 1 0 656 464 250 191 121 58.3 26.2 10.5 10 6.29 3.2628 1 0 147 169 90.1 58.2 40.2 21.7 4.21 2.9 3.35 0 12.4 29 1 0 72.6 7145.6 26.4 17.8 11.3 3.24 0 0 0 0 30 1 0 55.2 72 48.6 32.1 19.7 10.8 2.742.11 0 0 0 118 3 0 107 81.6 57.9 36.8 20.8 14.6 5.71 2.64 0 0 0 119 23.2 119 143 112 74 47.4 25.8 13.7 5.32 6.3 2.67 2.5 219 3 7 398 224 10588.5 58.5 36.7 11.4 3.55 3.35 0 0 2 mg 16 2 13.3 36 82 130 62 75.3 44.523.6 11.7 7.98 6.54 19.9 GROUND (B) 17 2 0 15.3 51.8 65.4 51.5 38.5 19.223.2 13.2 6.74 9.69 6.12 19 2 0 24.8 71.9 97.2 68.4 56.9 82.2 30 12.96.08 6.98 4.75 20 2 0 37.7 56.4 62.1 35.6 29.8 15.3 16.2 9.62 7.56 4.62.94 21 2 9.79 15.9 58.5 76.9 81.4 71.8 46.6 44.6 25.2 12.3 18.6 13.2 222 2.73 52.4 148 153 133 112 79.6 51.8 31.1 32.1 8.83 6.35 23 2 0 14.8 4086.2 68.9 60.6 28.7 24.6 6.77 5.73 5.9 3.11 24 2 5.37 44.1 82.4 74.149.3 40.2 22.4 15 11.8 10.6 8.07 4.88 25 2 5.02 85 135 125 156 57.6 57.539.6 27 21.6 11.7 10.4 26 2 0 48.5 63 64.1 48.4 31.2 35.1 22 12.3 10.66.82 6.47 27 2 3.35 264 443 356 263 186 163 75.7 39.7 29 22.5 191 28 2 044.4 101 126 102 74.3 36.7 34.3 19.5 11.4 12.5 7.18 29 2 0 28.8 42 68.245.6 37.4 20.1 77.3 7.37 150 4.26 5.86 30 2 10.8 4.57 41.2 64.9 69.155.5 31.7 26.9 9.25 7.28 5.94 5.82 118 1 3.98 14.8 61.9 70.1 63.9 48.438.4 30.6 17.8 10.7 9.07 7.09 219 1 2.85 121 227 153 116 223 104 45.127.8 14.7 11.6 5.66 10 mg. 16 3 0 0 21.2 65.8 87.9 62.3 77.2 106 10081.8 117 47.5 WHOLE (B) 17 3 0 23.7 23.3 74.6 80.2 76.1 75 118 87.7 48.769.9 44.6 20 3 71.2 8.96 34.3 47.5 40.8 38.7 37.5 79.8 70.3 40.6 45.933.4 21 3 0 0 10.3 27.7 33.2 30.2 66.3 103 83.6 132 125 115 22 3 0 5.3767.6 97.3 119 129 179 300 234 127 104 43.4 23 3 0 4.78 18.9 24.3 25.823.8 26.4 37.1 24.9 21.5 44.8 44.8 24 3 0 26.2 55.3 57.3 47.3 40.8 34.385.5 68.9 49.4 53.5 31.8 25 3 0 30.1 56 57.3 52.4 47.7 67.1 149 140 11738.1 30 26 3 0 2.74 24.8 36.8 34.3 33.1 44.4 57.1 74.8 56.2 86.2 63 27 30 69.5 175 270 274 193 167 302 222 321 335 193 28 3 0 55.9 37.6 88.2 114104 74.9 154 202 162 194 121 29 3 0 39.8 24 35.2 68.3 43.3 43.6 70.267.1 50.8 54.7 49.3 30 3 0 21.4 30.6 59.9 41.1 36.1 33.5 89.7 91.5 60.475.4 46.7 118 2 0 7.42 29 52.5 45.1 42.5 50.5 63 62.1 74.1 51.9 44.9 1191 0 12.8 66.1 83.2 87.8 72.1 123 125 69.8 40.5 79.5 62.4 219 2 0 18.233.5 71.1 84.7 85.1 80.8 255 200 149 113 60

Example 5 Sequestered Naltrexone HCl Beads

In Example 5, Naltrexone HCl beads for incorporation into capsules wereprepared having the following formulation in Table 5 below.

TABLE 5 Amt/unit Ingredients (mg) Step 1. Drug layering Naltrexone HCl2.1 Non-pareil beads (30/35 mesh) 39.98 Opadry Clear 0.4(Hydroxypropymethyl cellulose) Sodium ascorbate 0.027 Ascorbic acid 0.05Step 2. Anionic Eudragit L30D (dry) 2.164 polymer coat Triethyl Citrate0.433 Cabosil 0.108 Step 3. Sustained Eudragit RS30D (dry) 17.475release coat Triethyl citrate 3.495 Cabosil 0.874 Step 4. Seal coatOpadry Clear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total(on dry basis) 69.287Process:

-   1. Dissolve naltrexone HCl, ascorbic acid, sodium ascorbate and    Opadry Clear in water. Spray the drug solution onto non-pareil beads    in a fluid bed coater with Wurster insert.-   2. Disperse Eudragit L30D, Triethyl citrate, and Cabosil in water.    Spray the dispersion onto the drug-loaded beads in the fluid bed    coater.-   3. Disperse Eudragit RS30D, triethyl citrate, and Cabosil in water.    Spray the dispersion onto the beads in the fluid bed coater,-   4. Dissolve Opadty Clear in water. Spray the solution onto the beads    in the fluid bed coater.-   5. Cure the beads at 60° C. for 24 hours.

Example 6 Sequestered Naltrexone Multiparticulates

A naltrexone melt extruded multiparticulate formulation was prepared.The melt extruded multiparticulate formulation is listed in Table 6below.

TABLE 6 Ingredients Amt/Unit (mg) Naltrexone HCl 2.0 Eudragit RSPO 88.0Stearyl alcohol 15.0 Stearic acid 15.0 BHT 1.0 Total 121.0Process:

-   1. Blend milled Stearic acid, stearyl alcohol, Naltrexone HCl, BHT,    and Eudragit RSPO using a V-blender.-   2. Extrude the mixture using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate—4.2 kg/hr: vacuum—˜980 mBar    -   Conveyor—such that diameter of extrudate is 1 mm    -   Pelletizer—such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    114 mg and NMT 126 mg.

Example 7 Sequestered Naltrexone CR Beads

A naltrexone sustained release bead formulation was prepared which canbe incorporated into an opioid controlled release granulation and themixture is then compressed into tablets. The naltrexone controlledrelease bead formulation is listed in Table 7 below.

TABLE 7 Amt/unit* Ingredients (mg) Step 1. Drug layering Naltrexone HCl0.609 Non-pareil beads (30/35 mesh) 67.264 Opadry Clear 0.547 Step 2.Seal coat Eudragit L 2.545 Triethyl citrate 0.636 Glyceryl monostearate0.239 Step 3. Sustained Eudragit RS30D (dry) 43.789 release coatTriethyl citrate 8.758 Cabosil 2.189 Step 4. Seal coat Opadry Clear2.053 (Hydroxypropylmethyl cellulose) Cabosil 1.368 Total 130Process:

-   1. Dissolve naltrexone HCl and Opadry (HPMC) in water. Spray the    drug solution onto non-pareil beads in a fluid bed coater with    Wurster insert.-   2. Disperse Eudragit L, Triethyl citrate, and glyceryl monostearate    in water. Spray the dispersion onto the drug-loaded beads in the    fluid bed coater.-   3. Disperse Eudragit RS, triethyl citrate, and Cabosil in water.    Spray the dispersion onto the beads in the fluid bed coater.-   4. Dissolve Opadry in water. Spray the solution onto the beads in    the fluid bed coater.-   5. Cure the beads at 60° C. for 24 hours.

Example 8 Controlled Release Oxycodone 20 mg

In Example 8, a sustained release 20 mg oxycodone formulation(OxyContin® 20 mg) as prepared having the formulation listed in Table 8below.

TABLE 8 Ingredients Amt/Unit (mg) Oxycodone HCl 20.0 Spray Dried Lactose59.25 Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 StearylAlcohol 25.6 Talc 2.5 Magnesium Stearate 1.25 Opadry Pink Y-S-14518A 4.0Total 129.0Process:

-   1. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl. Spray Dried Lactose and Povidone using a fluid bed    granulator.-   2. Milling: Discharge the granulation and pass through a mill.-   3. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   4. Milling: Pass the cooled granulation through a mill.-   5. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   6. Compression: Compress the granulation into tablets using a tablet    press.-   7. Film coating: Apply an aqueous film coat to the tablets.

Example 9

In Example 9, naltrexone beads prepared in accordance with Example 7 areincorporated into the sustained release 20 mg oxycodone (OxyContin® 20mg) tablets prepared in accordance with Example 8 and having the formulalisted in Table 9 below.

TABLE 9 Amt/unit* Ingredients (mg) Step 1. Granulation Oxycodone HCl20.0 Spray Dried Lactose 59.25 Povidone 5.0 Eudragit RS30D (dry) 10.0Triacetin 2.0 Stearyl alcohol 25.0 Talc 2.5 Magnesium 1.25 Step 2.Combination OxyContin granulation (Example 3) 125 tablet Naltrexone CRbeads (Formula 2) 140Process:

-   1. Spray the Eudragit/triacetin dispersion onto the Oxycodone HCl,    spray dried lactose and povidone using a fluid bed granulator.-   2. Discharge the granulation and pass through a mill.-   3. Melt the stearyl alcohol and add to the milled granulation using    a mill. Allow to cool.-   4. Pass the cooled granulation through a mill.-   5. Lubricate the granulation with talc and magnesium stearate using    a mixer.-   6. Mix naltrexone beads with the above granulation and compress into    tablets.    Alternate Process:-   1. Spray the Eudragit/triacetin dispersion onto the Oxycodone HCl,    spray dried lactose and povidone using a fluid bed granulator.-   2. Discharge the granulation and pass through a mill.-   3. Mix naltrexone beads (example 2) with the above granulation in a    Hobar mixer.-   4. Melt the stearyl alcohol and add to the above mixture. Allow to    cool.-   5. Pass the cooled granulation through a mill.-   6. Lubricate the granulation with talc and magnesium stearate using    a mixer.-   7. Compress into tablets.

Example 10 Controlled Release Hydrocodone

A sustained release hydrocodone formulation was prepared having theformula in Table 10 below.

TABLE 10 Ingredients Amt/Unit (mg) Amt/Batch (g) Hydrocodone Bitartrate15.0 320.0 Eudragit RSPO 76.0 1520.0 Eudragit RLPO 4.0 80.0 StearylAlcohol 25.0 500.0 Total 120.0 2400.0Process:

-   1. Blend milled Stearyl Alcohol, Eudragit RLPO, Hydrocodone    Bitartrate, and Eudragit RSPO using a Hobart Mixer.-   2. Extrude the granulation using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm the head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate—40 g/min; vacuum—˜980 mBar    -   Conveyor-such that diameter of extrudate is 1 mm    -   Pelletizer—such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    (not less than) 114 mg and NMT (not more than) 126 mg.

The sequestered naltrexone formulation of Example 6 can be incorporatedin a capsule with the hydrocodone pellets. Preferably, the sequesterednaltrexone pellets are indistinguishable from the hydrocodone pellets.

Example 11 Controlled Release Oxycodone HCl Beads

A sustained release oxycodone HCl bead formulation was prepared havingthe formula in Table 11 below.

TABLE 11 Amt/unit* Ingredients (mg) Step 1. Drug layering Oxycodone HCl10.5 Non-pareil beads (30/35 mesh) 45.349 Opadry Clear 2.5 Step 2.Sustained Eudragit RS30D (dry) 7.206 release coat Eudragit RL30D (dry)0.379 Triethyl citrate 1.517 Cabosil 0.379 Step 3. Seal coat OpadryClear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total 70.0Process:

-   1. Dissolve oxycodone HCl and Opadry (HPMC) in water. Spray the drug    solution onto non-pareil beads in a fluid bed coater with Wurster    insert.-   2 Disperse Eudragit RS, Eudragit RL, triethyl citrate, and Cabosil    in water. Spray the dispersion onto the beads in the fluid bed    coater.-   3. Dissolve Opacity in water. Spray the solution onto the beads in    the fluid bed coater.-   4. Cure the beads at 60′C for 24 hours.

The sequestered naltrexone formulation of Example 5 can be incorporatedin a capsule with the oxycodone beads. Preferably, the sequesterednaltrexone beads are indistinguishable from the oxycodone beads.

Example 12 Controlled Release Hydromorphone

A sustained release hydromorphone HCl formulation was prepared havingthe formula in Table 12 below:

TABLE 12 Ingredients Amt/Unit (mg) Hydromorphone HCl 12.0 Eudragit RSPO76.5 Ethocel 4.5 Stearic acid 27.0 Total 120.0Process:

-   1. Blend milled Stearic acid, ethocel, Hydromorphone HCl, and    Eudragit RSPO using a V-blender.-   2. Extrude the mixture using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate—4.2 kg/hr; vacuum—˜980 mBar    -   Conveyor—such that diameter of extrudate is 1 mm    -   Pelletizer-such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    114 mg and NMT 126 mg.

The sequestered naltrexone formulation of Example 5 can be incorporatedin a capsule with the hydromorphone pellets. Preferably, the sequesterednaltrexone beads are indistinguishable from the hydromorphone HClpellets.

What is claimed is:
 1. An oral dosage form consisting of an opioidagonist, an opioid antagonist, one or more hydrophobic materials, andadditional pharmaceutically acceptable excipients, wherein the opioidantagonist is naltrexone or a pharmaceutically acceptable salt thereofand all of the opioid antagonist in the dosage form is sequestered withthe one or more hydrophobic materials such that the opioid antagonist issubstantially not released when the dosage form is administered intactbut is released in an effective amount to eliminate the euphoric effectof the opioid agonist when the dosage form is tampered with by means ofcrushing, shearing, grinding, chewing, dissolution in a solvent, heatingor any combination thereof, and wherein the dosage form which isadministered intact provides a mean Cmax of naltrexone of 30 pg/ml orless, based on oral administration of the dosage form containing 1 mg ofnaltrexone or the pharmaceutically acceptable salt thereof.
 2. Thedosage form of claim 1, wherein the mean Cmax of naltrexone is 15 pg/mlor less.
 3. The dosage form of claim 2, wherein the mean Cmax ofnaltrexone is 10 pg/ml or less.
 4. The dosage form of claim 3, whereinthe mean Cmax of naltrexone is 6 pg/ml or less.
 5. The dosage form ofclaim 4, wherein the mean Cmax of naltrexone is 3 pg/ml or less.
 6. Thedosage form of claim 5, wherein the Cmax of naltrexone is 1 pg/ml. 7.The dosage form of claim 1, wherein the opioid agonist is selected fromthe group consisting of morphine, hydromorphone, hydrocodone, oxycodone,codeine, meperidine, methadone, oxymorphone, buprenorphine, butorphanol,pharmaceutically acceptable salts thereof and mixtures thereof.
 8. Thedosage form of claim 1, wherein the opioid agonist is selected from thegroup consisting of oxycodone, hydrocodone and pharmaceuticallyacceptable salts thereof.
 9. The dosage form of claim 1, wherein theopioid antagonist is naltrexone hydrochloride.
 10. The dosage form ofclaim 9, wherein the opioid antagonist is sequestered by coating withthe one or more hydrophobic materials.
 11. The oral dosage form of claim1, wherein said tampering is by crushing.
 12. The dosage form of claim1, wherein the dosage form which is administered intact provides a meanTmax of naltrexone of about 0.75 hour to about 36 hours.
 13. The dosageform of claim 12, wherein the mean Tmax of naltrexone is from about 1hour to about 30 hours.
 14. The dosage form of claim 13, wherein themean Tmax of naltrexone is from about 2 hours to about 20 hours.
 15. Thedosage form of claim 14, wherein the mean Tmax of naltrexone is fromabout 3 hours to about 20 hours.
 16. The dosage form of claim 15,wherein the mean Tmax of naltrexone is from about 5 hours to about 15hours.
 17. The dosage form of claim 16, wherein the intact dosage formprovides a Tmax of naltrexone of about 6 hours to about 10 hours.
 18. Anoral dosage form consisting of an opioid agonist, an opioid antagonist,one or more hydrophobic materials, and pharmaceutically acceptableexcipients, wherein the opioid antagonist is naltrexone or apharmaceutically acceptable salt thereof and all of the opioidantagonist in the dosage form is sequestered with the one or morehydrophobic materials such that the opioid antagonist is substantiallynot released when the dosage form is administered intact but is releasedin an effective amount to eliminate the euphoric effect of the opioidagonist when the dosage form is tampered with by means of crushing,shearing, grinding, chewing, dissolution in a solvent, heating or anycombination thereof, and wherein the dosage form which is administeredintact provides a mean Cmax of naltrexone of 30 pg/ml or less and a meanAUCt of naltrexone of 400 pg*h/ml or less, based on oral administrationof the dosage form containing 1 mg of naltrexone or the pharmaceuticallyacceptable salt thereof.
 19. The dosage form of claim 18, wherein theAUCt of naltrexone is 350 pg*h/ml or less.
 20. The dosage form of claim18, wherein the opioid antagonist is naltrexone hydrochloride.
 21. Thedosage form of claim 20, wherein the opioid antagonist is sequestered bycoating with the one or more hydrophobic materials.
 22. The oral dosageform of claim 18, wherein said tampering is by crushing.